Vai ai contenuti. | Spostati sulla navigazione | Spostati sulla ricerca | Vai al menu | Contatti | Accessibilità

| Crea un account

Ciccarese, Francesco (2015) LKB1 deficiency sensitizes cancer cells to oxidative stress. [Tesi di dottorato]

Full text disponibile come:

[img]Documento PDF
Tesi non accessible fino a 2017 per motivi correlati alla proprietà intellettuale.
Visibile a: nessuno

3685Kb

Abstract (inglese)

Increased oxidative stress is a common feature of cancer cells. Uncontrolled proliferation, in fact, requires a profound metabolic remodelling, accompanied by altered redox status. Moreover, reactive oxygen species (ROS) are involved in cell signalling, tumor growth and metastasis. Recent studies suggest that increased oxidative stress in cancer cells could be exploited for therapeutic purposes. Understanding biochemical mechanisms involved in ROS generation and maintenance of the cellular antioxidant potential raises the possibility of therapeutic targeting these pathways. In our study, we investigated the role of LKB1/AMPK pathway in response to oxidative stress. LKB1 is a serine threonine kinase whose germ-line mutations are associated with the Peutz-Jeghers syndrome and somatically mutated in certain tumor types, including non-small cell lung cancer (NSCLC) and cervical carcinoma. Through the activation of AMP-activated protein kinase (AMPK), LKB1 modulates both anabolic and catabolic metabolic processes. We observed that LKB1 reconstitution in LKB1-deficient cancer cells significantly reduced expression of NADPH oxidase 1 (NOX1), a ROS-producing enzyme. LKB1+ cells showed reduced endogenous oxidative stress and increased resistance to exogenous oxidative stress, induced by hydrogen peroxide, cisplatin or irradiation, compared to LKB1- cells. Moreover, we observed that AMPK inhibition sensitized LKB1+ cells to oxidative stress, whereas NOX1 inhibition reduced ROS generation and increased resistance to exogenous oxidative stress. In lung cancer samples, LKB1 mutations were strongly associated with loss of LKB1 protein but the LKB1 status was not associated with response to bevacizumab and platinum-based chemotherapy in advanced NSCLC patients. Overall, these results indicate that LKB1, via the activation of AMPK and the down-regulation of NOX1, confers resistance to oxidative stress and impairs response of cancer cells to some chemotherapeutics and irradiation in vitro.

Abstract (italiano)

Una caratteristica comunemente riscontrata nel cancro è un aumento dello stress ossidativo, rispetto al corrispondente tessuto sano. Infatti, la proliferazione incontrollata delle cellule tumorali richiede un importante rimodellamento metabolico, che si accompagna ad alterazioni dell’equilibrio redox. Le specie reattive dell'ossigeno (ROS) risultano, inoltre, coinvolte nelle vie di segnalazione cellulare, nella crescita tumorale e nella metastatizzazione del cancro.
Recenti studi suggeriscono che l’aumento dello stress ossidativo possa essere sfruttato a scopi terapeutici, per eliminare selettivamente le cellule tumorali. La comprensione dei meccanismi molecolari che governano la produzione di ROS o il mantenimento del potenziale antiossidante delle cellule potrebbe, infatti, rendere possibile un’azione diretta su questi stessi meccanismi a scopo terapeutico.
In questo lavoro di tesi abbiamo valutato il ruolo della via di segnalazione LKB1/AMPK nella risposta allo stress ossidativo. LKB1 è una serina/treonina chinasi, le cui mutazioni sono state associate alla sindrome ereditaria di Peutz-Jeghers; risulta, inoltre, mutata sporadicamente in alcuni tipi di cancro, tra cui il carcinoma polmonare non a piccole cellule (NSCLC) e il carcinoma della cervice uterina. Attraverso l’attivazione della chinasi AMPK, LKB1 modula sia processi anabolici, sia processi catabolici. I nostri dati hanno dimostrato come la re-introduzione di LKB1 in cellule tumorali LKB1-mutate riduce significativamente l’espressione della NADPH ossidasi 1 (NOX1), un enzima coinvolto nella produzione di ROS. Le cellule LKB1+ manifestano, inoltre, uno stress ossidativo endogeno ridotto, rispetto alle cellule LKB1-, che si accompagna ad un’aumentata resistenza allo stress ossidativo esogeno, indotto dal perossido di idrogeno, dal cisplatino o dall’irradiazione. Abbiamo osservato che l’inibizione di AMPK porta ad una sensibilizzazione delle cellule LKB1+ allo stress ossidativo, suggerendo che la loro ridotta sensibilità sia mediata da AMPK; inoltre, l’inibizione di NOX1 nelle cellule LKB1- si accompagna ad una ridotta produzione di ROS e ad una maggiore resistenza allo stress ossidativo.
Infine, in campioni di carcinoma polmonare, le mutazioni di LKB1 sono risultate fortemente associate alla perdita della proteina LKB1; tuttavia, lo status di LKB1 non è risultato associato alla risposta al bevacizumab o alla chemioterapia con derivati del platino in pazienti affetti da NSCLC avanzato.
Nel loro insieme, questi risultati indicano che LKB1, attraverso l’attivazione di AMPK e la ridotta espressione di NOX1, conferisce resistenza allo stress ossidativo nelle cellule tumorali, compromettendo la risposta ad agenti chemioterapici o all’irradiazione in vitro, i quali modulano l'equilibrio ossidativo della cellula.

Aggiungi a RefWorks
Tipo di EPrint:Tesi di dottorato
Relatore:Indraccolo, Stefano
Dottorato (corsi e scuole):Ciclo 27 > scuole 27 > ONCOLOGIA E ONCOLOGIA CHIRURGICA
Data di deposito della tesi:30 Gennaio 2015
Anno di Pubblicazione:02 Febbraio 2015
Parole chiave (italiano / inglese):NSCLC, stress ossidativo, LKB1, AMPK, NOX1, cisplatino, irradiazione
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/06 Oncologia medica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche
Codice ID:7816
Depositato il:16 Nov 2015 11:29
Simple Metadata
Full Metadata
EndNote Format

Bibliografia

I riferimenti della bibliografia possono essere cercati con Cerca la citazione di AIRE, copiando il titolo dell'articolo (o del libro) e la rivista (se presente) nei campi appositi di "Cerca la Citazione di AIRE".
Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

Adams, J., Chen, Z. P., Van Denderen, B. J., Morton, C. J., Parker, M. W., Witters, L. A., Stapleton, D., and Kemp, B. E. (2004). Intrasteric control of AMPK via the gamma1 subunit AMP allosteric regulatory site. Protein Sci 13, 155-165. Cerca con Google

Alessi, D. R., Sakamoto, K., and Bayascas, J. R. (2006). LKB1-dependent signaling pathways. Annu Rev Biochem 75, 137-163. Cerca con Google

Alexandre, J., Hu, Y., Lu, W., Pelicano, H., and Huang, P. (2007). Novel action of paclitaxel against cancer cells: bystander effect mediated by reactive oxygen species. Cancer Res 67, 3512-3517. Cerca con Google

Ansari, M. A., and Scheff, S. W. (2011). NADPH-oxidase activation and cognition in Alzheimer disease progression. Free Radic Biol Med 51, 171-178. Cerca con Google

Austin, S., and St-Pierre, J. (2012). PGC1alpha and mitochondrial metabolism--emerging concepts and relevance in ageing and neurodegenerative disorders. J Cell Sci 125, 4963-4971. Cerca con Google

Baas, A. F., Smit, L., and Clevers, H. (2004). LKB1 tumor suppressor protein: PARtaker in cell polarity. Trends Cell Biol 14, 312-319. Cerca con Google

Bedard, K., and Krause, K. H. (2007). The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87, 245-313. Cerca con Google

Boeckman, H. J., Trego, K. S., and Turchi, J. J. (2005). Cisplatin sensitizes cancer cells to ionizing radiation via inhibition of nonhomologous end joining. Mol Cancer Res 3, 277-285. Cerca con Google

Borek, C. (2004). Antioxidants and radiation therapy. J Nutr 134, 3207S-3209S. Cerca con Google

Boudeau, J., Sapkota, G., and Alessi, D. R. (2003). LKB1, a protein kinase regulating cell proliferation and polarity. FEBS Lett 546, 159-165. Cerca con Google

Canto, C., and Auwerx, J. (2009). PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 20, 98-105. Cerca con Google

Cardone, L., Bardelli, A., and Avvedimento, V. E. (2012). Activation of beta-catenin by oncogenic PIK3CA and EGFR promotes resistance to glucose deprivation by inducing a strong antioxidant response. PLoS One 7, e37526. Cerca con Google

Carretero, J., Medina, P. P., Pio, R., Montuenga, L. M., and Sanchez-Cespedes, M. (2004). Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor suppressor gene. Oncogene 23, 4037-4040. Cerca con Google

Casares, C., Ramirez-Camacho, R., Trinidad, A., Roldan, A., Jorge, E., and Garcia-Berrocal, J. R. (2012). Reactive oxygen species in apoptosis induced by cisplatin: review of physiopathological mechanisms in animal models. Eur Arch Otorhinolaryngol 269, 2455-2459. Cerca con Google

Charloux, A., Quoix, E., Wolkove, N., Small, D., Pauli, G., and Kreisman, H. (1997). The increasing incidence of lung adenocarcinoma: reality or artefact? A review of the epidemiology of lung adenocarcinoma. Int J Epidemiol 26, 14-23. Cerca con Google

Chen, H., Goldberg, M. S., and Villeneuve, P. J. (2008). A systematic review of the relation between long-term exposure to ambient air pollution and chronic diseases. Rev Environ Health 23, 243-297. Cerca con Google

Chen, H. H., and Kuo, M. T. (2010). Role of glutathione in the regulation of Cisplatin resistance in cancer chemotherapy. Met Based Drugs 2010. Cerca con Google

Clegg, A., Scott, D. A., Hewitson, P., Sidhu, M., and Waugh, N. (2002). Clinical and cost effectiveness of paclitaxel, docetaxel, gemcitabine, and vinorelbine in non-small cell lung cancer: a systematic review. Thorax 57, 20-28. Cerca con Google

Costanzo, R., Piccirillo, M. C., Sandomenico, C., Carillio, G., Montanino, A., Daniele, G., Giordano, P., Bryce, J., De Feo, G., Di Maio, M., et al. (2011). Gefitinib in non small cell lung cancer. J Biomed Biotechnol 2011, 815269. Cerca con Google

D’Arcangelo, M., and Cappuzzo, F. (2012). K-Ras Mutations in Non-Small-Cell Lung Cancer: Prognostic and Predictive Value. ISRN Molecular Biology 2012, 8. Cerca con Google

Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D. M., Morgan, M. B., et al. (2008). Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069-1075. Cerca con Google

Dong, G. Z., Jang, E. J., Kang, S. H., Cho, I. J., Park, S. D., Kim, S. C., and Kim, Y. W. (2013a). Red ginseng abrogates oxidative stress via mitochondria protection mediated by LKB1-AMPK pathway. BMC Complement Altern Med 13, 64. Cerca con Google

Dong, L. X., Sun, L. L., Zhang, X., Pan, L., Lian, L. J., Chen, Z., and Zhong, D. S. (2013b). Negative regulation of mTOR activity by LKB1-AMPK signaling in non-small cell lung cancer cells. Acta Pharmacol Sin 34, 314-318. Cerca con Google

Edderkaoui, M., Nitsche, C., Zheng, L., Pandol, S. J., Gukovsky, I., and Gukovskaya, A. S. (2013). NADPH oxidase activation in pancreatic cancer cells is mediated through Akt-dependent up-regulation of p22phox. J Biol Chem 288, 36259. Cerca con Google

El Sayed, S. M., El-Magd, R. M. A., Shishido, Y., Chung, S. P., Diem, T. H., Sakai, T., Watanabe, H., Kagami, S., and Fukui, K. (2012). 3-Bromopyruvate antagonizes effects of lactate and pyruvate, synergizes with citrate and exerts novel anti-glioma effects. J Bioenerg Biomembr 44, 61-79. Cerca con Google

El Sayed, S. M., Mahmoud, A. A., El Sawy, S. A., Abdelaal, E. A., Fouad, A. M., Yousif, R. S., Hashim, M. S., Hemdan, S. B., Kadry, Z. M., Abdelmoaty, M. A., et al. Warburg effect increases steady-state ROS condition in cancer cells through decreasing their antioxidant capacities (Anticancer effects of 3-bromopyruvate through antagonizing Warburg effect). Medical Hypotheses 81, 866-870. Cerca con Google

Fack, F., Espedal, H., Keunen, O., Golebiewska, A., Obad, N., Harter, P. N., Mittelbronn, M., Bahr, O., Weyerbrock, A., Stuhr, L., et al. (2015). Bevacizumab treatment induces metabolic adaptation toward anaerobic metabolism in glioblastomas. Acta Neuropathol 129, 115-131. Cerca con Google

Fan, C. Y., Katsuyama, M., and Yabe-Nishimura, C. (2005). PKCdelta mediates up-regulation of NOX1, a catalytic subunit of NADPH oxidase, via transactivation of the EGF receptor: possible involvement of PKCdelta in vascular hypertrophy. Biochem J 390, 761-767. Cerca con Google

Faubert, B., Boily, G., Izreig, S., Griss, T., Samborska, B., Dong, Z., Dupuy, F., Chambers, C., Fuerth, B. J., Viollet, B., et al. (2013). AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 17, 113-124. Cerca con Google

Faubert, B., Vincent, E. E., Griss, T., Samborska, B., Izreig, S., Svensson, R. U., Mamer, O. A., Avizonis, D., Shackelford, D. B., Shaw, R. J., and Jones, R. G. (2014). Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1alpha. Proc Natl Acad Sci U S A 111, 2554-2559. Cerca con Google

Faubert, B., Vincent, E. E., Poffenberger, M. C., and Jones, R. G. (2015). The AMP-activated protein kinase (AMPK) and cancer: many faces of a metabolic regulator. Cancer Lett 356, 165-170. Cerca con Google

Feng, Y., Wang, Y., Wang, Z., Fang, Z., Li, F., Gao, Y., Liu, H., Xiao, T., Zhou, Y., Zhai, Q., et al. (2012). The CRTC1-NEDD9 signaling axis mediates lung cancer progression caused by LKB1 loss. Cancer Res 72, 6502-6511. Cerca con Google

Folkman, J. (1992). The role of angiogenesis in tumor growth. Semin Cancer Biol 3, 65-71. Cerca con Google

Folkman, J. (2002). Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29, 15-18. Cerca con Google

Fuld, A. D., Dragnev, K. H., and Rigas, J. R. (2010). Pemetrexed in advanced non-small-cell lung cancer. Expert Opin Pharmacother 11, 1387-1402. Cerca con Google

Gill, R. K., Yang, S. H., Meerzaman, D., Mechanic, L. E., Bowman, E. D., Jeon, H. S., Roy Chowdhuri, S., Shakoori, A., Dracheva, T., Hong, K. M., et al. (2011). Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer. Oncogene 30, 3784-3791. Cerca con Google

Gorrini, C., Harris, I. S., and Mak, T. W. (2013). Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12, 931-947. Cerca con Google

Gupta, S. C., Singh, R., Pochampally, R., Watabe, K., and Mo, Y. Y. (2014). Acidosis promotes invasiveness of breast cancer cells through ROS-AKT-NF-kappaB pathway. Oncotarget 5, 12070-12082. Cerca con Google

Hamanaka, R. B., and Chandel, N. S. (2010). Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem Sci 35, 505-513. Cerca con Google

Hardie, D. G. (2004). The AMP-activated protein kinase pathway--new players upstream and downstream. J Cell Sci 117, 5479-5487. Cerca con Google

Hardie, D. G., and Carling, D. (1997). The AMP-activated protein kinase--fuel gauge of the mammalian cell? Eur J Biochem 246, 259-273. Cerca con Google

Hardie, D. G., and MacKintosh, R. W. (1992). AMP-activated protein kinase--an archetypal protein kinase cascade? Bioessays 14, 699-704. Cerca con Google

Hatton, M. Q., and Martin, J. E. (2010). Continuous hyperfractionated accelerated radiotherapy (CHART) and non-conventionally fractionated radiotherapy in the treatment of non-small cell lung cancer: a review and consideration of future directions. Clin Oncol (R Coll Radiol) 22, 356-364. Cerca con Google

Hecht, S. S. (2012). Lung carcinogenesis by tobacco smoke. Int J Cancer 131, 2724-2732. Cerca con Google

Hemminki, A., Markie, D., Tomlinson, I., Avizienyte, E., Roth, S., Loukola, A., Bignell, G., Warren, W., Aminoff, M., Hoglund, P., et al. (1998). A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391, 184-187. Cerca con Google

Huang, X., Wullschleger, S., Shpiro, N., McGuire, V. A., Sakamoto, K., Woods, Y. L., McBurnie, W., Fleming, S., and Alessi, D. R. (2008). Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J 412, 211-221. Cerca con Google

Iacobini, M., Menichelli, A., Palumbo, G., Multari, G., Werner, B., and Del Principe, D. (2001). Involvement of oxygen radicals in cytarabine-induced apoptosis in human polymorphonuclear cells. Biochem Pharmacol 61, 1033-1040. Cerca con Google

Inazuka, F., Sugiyama, N., Tomita, M., Abe, T., Shioi, G., and Esumi, H. (2012). Muscle-specific knock-out of NUAK family SNF1-like kinase 1 (NUAK1) prevents high fat diet-induced glucose intolerance. J Biol Chem 287, 16379-16389. Cerca con Google

Inge, L. J., Friel, J. M., Richer, A. L., Fowler, A. J., Whitsett, T., Smith, M. A., Tran, N. L., and Bremner, R. M. (2014). LKB1 inactivation sensitizes non-small cell lung cancer to pharmacological aggravation of ER stress. Cancer Lett 352, 187-195. Cerca con Google

Jain, R. K. (2005). Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58-62. Cerca con Google

Jairam, V., Uchida, K., and Narayanaswami, V. (2012). Pathophysiology of Lipoprotein Oxidation). Cerca con Google

Jaramillo, M. C., and Zhang, D. D. (2013). The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev 27, 2179-2191. Cerca con Google

Jeon, S. M., Chandel, N. S., and Hay, N. (2012). AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661-665. Cerca con Google

Ji, H., Ramsey, M. R., Hayes, D. N., Fan, C., McNamara, K., Kozlowski, P., Torrice, C., Wu, M. C., Shimamura, T., Perera, S. A., et al. (2007). LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807-810. Cerca con Google

Jian, S. F., Hsiao, C. C., Chen, S. Y., Weng, C. C., Kuo, T. L., Wu, D. C., Hung, W. C., and Cheng, K. H. (2014). Utilization of liquid chromatography mass spectrometry analyses to identify LKB1-APC interaction in modulating Wnt/beta-catenin pathway of lung cancer cells. Mol Cancer Res 12, 622-635. Cerca con Google

Jubb, A. M., and Harris, A. L. (2010). Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol 11, 1172-1183. Cerca con Google

Kelland, L. R. (2000). Preclinical perspectives on platinum resistance. Drugs 59 Suppl 4, 1-8; discussion 37-38. Cerca con Google

Kemp, B. E., Stapleton, D., Campbell, D. J., Chen, Z. P., Murthy, S., Walter, M., Gupta, A., Adams, J. J., Katsis, F., van Denderen, B., et al. (2003). AMP-activated protein kinase, super metabolic regulator. Biochem Soc Trans 31, 162-168. Cerca con Google

Kim, H. S., Mendiratta, S., Kim, J., Pecot, C. V., Larsen, J. E., Zubovych, I., Seo, B. Y., Eskiocak, B., Chung, H., McMillan, E., et al. (2013). Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer. Cell 155, 552-566. Cerca con Google

Kim, M. J., Nagy, L. E., and Park, P. H. (2014). Globular adiponectin inhibits ethanol-induced reactive oxygen species production through modulation of NADPH oxidase in macrophages: involvement of liver kinase B1/AMP-activated protein kinase pathway. Mol Pharmacol 86, 284-296. Cerca con Google

Kirshner, J. R., He, S., Balasubramanyam, V., Kepros, J., Yang, C. Y., Zhang, M., Du, Z., Barsoum, J., and Bertin, J. (2008). Elesclomol induces cancer cell apoptosis through oxidative stress. Mol Cancer Ther 7, 2319-2327. Cerca con Google

Klutho, P. J., Costanzo-Garvey, D. L., and Lewis, R. E. (2011). Regulation of glucose homeostasis by KSR1 and MARK2. PLoS One 6, e29304. Cerca con Google

Koivunen, J. P., Kim, J., Lee, J., Rogers, A. M., Park, J. O., Zhao, X., Naoki, K., Okamoto, I., Nakagawa, K., Yeap, B. Y., et al. (2008). Mutations in the LKB1 tumour suppressor are frequently detected in tumours from Caucasian but not Asian lung cancer patients. Br J Cancer 99, 245-252. Cerca con Google

Kong, S. S., Liu, J. J., Yu, X. J., Lu, Y., and Zang, W. J. (2012). Protection against ischemia-induced oxidative stress conferred by vagal stimulation in the rat heart: involvement of the AMPK-PKC pathway. Int J Mol Sci 13, 14311-14325. Cerca con Google

Kumar, B., Koul, S., Khandrika, L., Meacham, R. B., and Koul, H. K. (2008). Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. Cancer Res 68, 1777-1785. Cerca con Google

Kumar, C., Igbaria, A., D'Autreaux, B., Planson, A. G., Junot, C., Godat, E., Bachhawat, A. K., Delaunay-Moisan, A., and Toledano, M. B. (2011). Glutathione revisited: a vital function in iron metabolism and ancillary role in thiol-redox control. EMBO J 30, 2044-2056. Cerca con Google

Kusakai, G., Suzuki, A., Ogura, T., Kaminishi, M., and Esumi, H. (2004). Strong association of ARK5 with tumor invasion and metastasis. J Exp Clin Cancer Res 23, 263-268. Cerca con Google

Lau, A., Villeneuve, N. F., Sun, Z., Wong, P. K., and Zhang, D. D. (2008). Dual roles of Nrf2 in cancer. Pharmacol Res 58, 262-270. Cerca con Google

Launonen, V. (2005). Mutations in the human LKB1/STK11 gene. Hum Mutat 26, 291-297. Cerca con Google

Lee, H. R., Cho, J. M., Shin, D. H., Yong, C. S., Choi, H. G., Wakabayashi, N., and Kwak, M. K. (2008). Adaptive response to GSH depletion and resistance to L-buthionine-(S,R)-sulfoximine: involvement of Nrf2 activation. Mol Cell Biochem 318, 23-31. Cerca con Google

Li, X., Fang, P., Mai, J., Choi, E. T., Wang, H., and Yang, X. F. (2013). Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol 6, 19. Cerca con Google

Liang, J., and Mills, G. B. (2013). AMPK: a contextual oncogene or tumor suppressor? Cancer Res 73, 2929-2935. Cerca con Google

Liang, X., Li, Z. L., Jiang, L. L., Guo, Q. Q., Liu, M. J., and Nan, K. J. (2014). Suppression of lung cancer cell invasion by LKB1 is due to the downregulation of tissue factor and vascular endothelial growth factor, partly dependent on SP1. Int J Oncol 44, 1989-1997. Cerca con Google

Liang, X., Wang, P., Gao, Q., Xiang, T., and Tao, X. (2010). Endogenous LKB1 knockdown accelerates G(1)/S transition through p53 and p16 pathways. Cancer Biol Ther 9, 156-160. Cerca con Google

Liu, M., Ma, S., Hou, Y., Liang, B., Su, X., and Liu, X. (2014). Synergistic killing of lung cancer cells by cisplatin and radiation via autophagy and apoptosis. Oncol Lett 7, 1903-1910. Cerca con Google

Liu, Y., Marks, K., Cowley, G. S., Carretero, J., Liu, Q., Nieland, T. J., Xu, C., Cohoon, T. J., Gao, P., Zhang, Y., et al. (2013). Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1-mutant lung cancer. Cancer Discov 3, 870-879. Cerca con Google

Lu, S. C. (2009). Regulation of glutathione synthesis. Mol Aspects Med 30, 42-59. Cerca con Google

Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350, 2129-2139. Cerca con Google

Marnett, L. J. (1999). Lipid peroxidation-DNA damage by malondialdehyde. Mutat Res 424, 83-95. Cerca con Google

Martelli, M. P., Sozzi, G., Hernandez, L., Pettirossi, V., Navarro, A., Conte, D., Gasparini, P., Perrone, F., Modena, P., Pastorino, U., et al. (2009). EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. Am J Pathol 174, 661-670. Cerca con Google

Matsumoto, S., Iwakawa, R., Takahashi, K., Kohno, T., Nakanishi, Y., Matsuno, Y., Suzuki, K., Nakamoto, M., Shimizu, E., Minna, J. D., and Yokota, J. (2007). Prevalence and specificity of LKB1 genetic alterations in lung cancers. Oncogene 26, 5911-5918. Cerca con Google

McCarty, M. F., Barroso-Aranda, J., and Contreras, F. (2009). AMP-activated kinase may suppress NADPH oxidase activation in vascular tissues. Med Hypotheses 72, 468-470. Cerca con Google

McGuirk, S., Gravel, S. P., Deblois, G., Papadopoli, D. J., Faubert, B., Wegner, A., Hiller, K., Avizonis, D., Akavia, U. D., Jones, R. G., et al. (2013). PGC-1alpha supports glutamine metabolism in breast cancer. Cancer Metab 1, 22. Cerca con Google

Namiki, T., Coelho, S. G., and Hearing, V. J. (2011a). NUAK2: an emerging acral melanoma oncogene. Oncotarget 2, 695-704. Cerca con Google

Namiki, T., Tanemura, A., Valencia, J. C., Coelho, S. G., Passeron, T., Kawaguchi, M., Vieira, W. D., Ishikawa, M., Nishijima, W., Izumo, T., et al. (2011b). AMP kinase-related kinase NUAK2 affects tumor growth, migration, and clinical outcome of human melanoma. Proc Natl Acad Sci U S A 108, 6597-6602. Cerca con Google

Nardo, G., Favaro, E., Curtarello, M., Moserle, L., Zulato, E., Persano, L., Rossi, E., Esposito, G., Crescenzi, M., Casanovas, O., et al. (2011). Glycolytic phenotype and AMP kinase modify the pathologic response of tumor xenografts to VEGF neutralization. Cancer Res 71, 4214-4225. Cerca con Google

O'Reilly, K. M., McLaughlin, A. M., Beckett, W. S., and Sime, P. J. (2007). Asbestos-related lung disease. Am Fam Physician 75, 683-688. Cerca con Google

Ojuka, E. O. (2004). Role of calcium and AMP kinase in the regulation of mitochondrial biogenesis and GLUT4 levels in muscle. Proc Nutr Soc 63, 275-278. Cerca con Google

Okon, I. S., Coughlan, K. A., and Zou, M. H. (2014). Liver kinase B1 expression promotes phosphatase activity and abrogation of receptor tyrosine kinase phosphorylation in human cancer cells. J Biol Chem 289, 1639-1648. Cerca con Google

Okuda, K., Sasaki, H., Hikosaka, Y., Kawano, O., Moriyama, S., Yano, M., and Fujii, Y. (2011). LKB1 gene alterations in surgically resectable adenocarcinoma of the lung. Surg Today 41, 107-110. Cerca con Google

Osoegawa, A., Kometani, T., Nosaki, K., Ondo, K., Hamatake, M., Hirai, F., Seto, T., Sugio, K., and Ichinose, Y. (2011). LKB1 mutations frequently detected in mucinous bronchioloalveolar carcinoma. Jpn J Clin Oncol 41, 1132-1137. Cerca con Google

Park, J., Yoon, Y. S., Han, H. S., Kim, Y. H., Ogawa, Y., Park, K. G., Lee, C. H., Kim, S. T., and Koo, S. H. (2014). SIK2 is critical in the regulation of lipid homeostasis and adipogenesis in vivo. Diabetes 63, 3659-3673. Cerca con Google

Parzefall, W., Freiler, C., Lorenz, O., Koudelka, H., Riegler, T., Nejabat, M., Kainzbauer, E., Grasl-Kraupp, B., and Schulte-Hermann, R. (2014). Superoxide deficiency attenuates promotion of hepatocarcinogenesis by cytotoxicity in NADPH oxidase knockout mice. Arch Toxicol. Cerca con Google

Pillai, R. N., and Ramalingam, S. S. (2012). The biology and clinical features of non-small cell lung cancers with EML4-ALK translocation. Curr Oncol Rep 14, 105-110. Cerca con Google

Plate, K. H., Breier, G., Weich, H. A., and Risau, W. (1992). Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359, 845-848. Cerca con Google

Raj, L., Ide, T., Gurkar, A. U., Foley, M., Schenone, M., Li, X., Tolliday, N. J., Golub, T. R., Carr, S. A., Shamji, A. F., et al. (2011). Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475, 231-234. Cerca con Google

Remacle, J., Raes, M., Toussaint, O., Renard, P., and Rao, G. (1995). Low levels of reactive oxygen species as modulators of cell function. Mutat Res 316, 103-122. Cerca con Google

Ren, J. H., He, W. S., Yan, G. L., Jin, M., Yang, K. Y., and Wu, G. (2012). EGFR mutations in non-small-cell lung cancer among smokers and non-smokers: a meta-analysis. Environ Mol Mutagen 53, 78-82. Cerca con Google

Reznick, R. M., and Shulman, G. I. (2006). The role of AMP-activated protein kinase in mitochondrial biogenesis. J Physiol 574, 33-39. Cerca con Google

Rune, A., Osler, M. E., Fritz, T., and Zierath, J. R. (2009). Regulation of skeletal muscle sucrose, non-fermenting 1/AMP-activated protein kinase-related kinase (SNARK) by metabolic stress and diabetes. Diabetologia 52, 2182-2189. Cerca con Google

Saigusa, S., Inoue, Y., Tanaka, K., Toiyama, Y., Kawamura, M., Okugawa, Y., Okigami, M., Hiro, J., Uchida, K., Mohri, Y., and Kusunoki, M. (2013). Significant correlation between LKB1 and LGR5 gene expression and the association with poor recurrence-free survival in rectal cancer after preoperative chemoradiotherapy. J Cancer Res Clin Oncol 139, 131-138. Cerca con Google

Sakurai, T., and Kudo, M. (2011). Signaling pathways governing tumor angiogenesis. Oncology 81 Suppl 1, 24-29. Cerca con Google

Sanchez-Cespedes, M. (2007). A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome. Oncogene 26, 7825-7832. Cerca con Google

Sanli, T., Steinberg, G. R., Singh, G., and Tsakiridis, T. (2014). AMP-activated protein kinase (AMPK) beyond metabolism: a novel genomic stress sensor participating in the DNA damage response pathway. Cancer Biol Ther 15, 156-169. Cerca con Google

Scaltriti, M., and Baselga, J. (2006). The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res 12, 5268-5272. Cerca con Google

Scandalios, J. G. (2002). Oxidative stress responses--what have genome-scale studies taught us? Genome Biol 3, REVIEWS1019. Cerca con Google

Schreck, R., Albermann, K., and Baeuerle, P. A. (1992). Nuclear factor kappa B: an oxidative stress-responsive transcription factor of eukaryotic cells (a review). Free Radic Res Commun 17, 221-237. Cerca con Google

Segal, A. W. (2005). How neutrophils kill microbes. Annu Rev Immunol 23, 197-223. Cerca con Google

Sen, C. K. (2000). Cellular thiols and redox-regulated signal transduction. Curr Top Cell Regul 36, 1-30. Cerca con Google

Shackelford, D. B., Abt, E., Gerken, L., Vasquez, D. S., Seki, A., Leblanc, M., Wei, L., Fishbein, M. C., Czernin, J., Mischel, P. S., and Shaw, R. J. (2013). LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23, 143-158. Cerca con Google

Shaw, R. J. (2009). LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol (Oxf) 196, 65-80. Cerca con Google

Shaw, R. J., Bardeesy, N., Manning, B. D., Lopez, L., Kosmatka, M., DePinho, R. A., and Cantley, L. C. (2004). The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6, 91-99. Cerca con Google

Shin, D. H., Choi, Y. J., and Park, J. W. (2014). SIRT1 and AMPK mediate hypoxia-induced resistance of non-small cell lung cancers to cisplatin and doxorubicin. Cancer Res 74, 298-308. Cerca con Google

Shin, S. M., Cho, I. J., and Kim, S. G. (2009). Resveratrol protects mitochondria against oxidative stress through AMP-activated protein kinase-mediated glycogen synthase kinase-3beta inhibition downstream of poly(ADP-ribose)polymerase-LKB1 pathway. Mol Pharmacol 76, 884-895. Cerca con Google

Siddik, Z. H. (2003). Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22, 7265-7279. Cerca con Google

Soda, M., Choi, Y. L., Enomoto, M., Takada, S., Yamashita, Y., Ishikawa, S., Fujiwara, S., Watanabe, H., Kurashina, K., Hatanaka, H., et al. (2007). Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561-566. Cerca con Google

Soengas, M. S. (2012). Mitophagy or how to control the Jekyll and Hyde embedded in mitochondrial metabolism: implications for melanoma progression and drug resistance. Pigment Cell Melanoma Res 25, 721-731. Cerca con Google

Song, P., Xie, Z., Wu, Y., Xu, J., Dong, Y., and Zou, M. H. (2008). Protein kinase Czeta-dependent LKB1 serine 428 phosphorylation increases LKB1 nucleus export and apoptosis in endothelial cells. J Biol Chem 283, 12446-12455. Cerca con Google

Sterba, M., Popelova, O., Vavrova, A., Jirkovsky, E., Kovarikova, P., Gersl, V., and Simunek, T. (2013). Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxid Redox Signal 18, 899-929. Cerca con Google

Stordal, B., and Davey, M. (2007). Understanding cisplatin resistance using cellular models. IUBMB Life 59, 696-699. Cerca con Google

Strazisar, M., Mlakar, V., Rott, T., and Glavac, D. (2009). Somatic alterations of the serine/threonine kinase LKB1 gene in squamous cell (SCC) and large cell (LCC) lung carcinoma. Cancer Invest 27, 407-416. Cerca con Google

Sun, C., Tian, L., Nie, J., Zhang, H., Han, X., and Shi, Y. (2012). Inactivation of MARK4, an AMP-activated protein kinase (AMPK)-related kinase, leads to insulin hypersensitivity and resistance to diet-induced obesity. J Biol Chem 287, 38305-38315. Cerca con Google

Suthanthiran, M., Anderson, M. E., Sharma, V. K., and Meister, A. (1990). Glutathione regulates activation-dependent DNA synthesis in highly purified normal human T lymphocytes stimulated via the CD2 and CD3 antigens. Proc Natl Acad Sci U S A 87, 3343-3347. Cerca con Google

Suzuki, A., Kusakai, G., Kishimoto, A., Lu, J., Ogura, T., Lavin, M. F., and Esumi, H. (2003). Identification of a novel protein kinase mediating Akt survival signaling to the ATM protein. J Biol Chem 278, 48-53. Cerca con Google

Toulany, M., Mihatsch, J., Holler, M., Chaachouay, H., and Rodemann, H. P. (2014). Cisplatin-mediated radiosensitization of non-small cell lung cancer cells is stimulated by ATM inhibition. Radiother Oncol 111, 228-236. Cerca con Google

Townsend, D. M., and Tew, K. D. (2003). The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene 22, 7369-7375. Cerca con Google

Trachootham, D., Alexandre, J., and Huang, P. (2009). Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8, 579-591. Cerca con Google

Traverso, N., Ricciarelli, R., Nitti, M., Marengo, B., Furfaro, A. L., Pronzato, M. A., Marinari, U. M., and Domenicotti, C. (2013). Role of glutathione in cancer progression and chemoresistance. Oxid Med Cell Longev 2013, 972913. Cerca con Google

Tsai, L. H., Wu, J. Y., Cheng, Y. W., Chen, C. Y., Sheu, G. T., Wu, T. C., and Lee, H. (2014). The MZF1/c-MYC axis mediates lung adenocarcinoma progression caused by wild-type lkb1 loss. Oncogene. Cerca con Google

Tsang, W. P., Chau, S. P., Kong, S. K., Fung, K. P., and Kwok, T. T. (2003). Reactive oxygen species mediate doxorubicin induced p53-independent apoptosis. Life Sci 73, 2047-2058. Cerca con Google

Ui, A., Ogiwara, H., Nakajima, S., Kanno, S., Watanabe, R., Harata, M., Okayama, H., Harris, C. C., Yokota, J., Yasui, A., and Kohno, T. (2014). Possible involvement of LKB1-AMPK signaling in non-homologous end joining. Oncogene 33, 1640-1648. Cerca con Google

van den Heuvel, A. P. J., Jing, J., Wooster, R. F., and Bachman, K. E. (2012). Analysis of glutamine dependency in non-small cell lung cancer. Cancer Biology & Therapy 13, 1185-1194. Cerca con Google

Violi, F., Basili, S., Nigro, C., and Pignatelli, P. (2009). Role of NADPH oxidase in atherosclerosis. Future Cardiol 5, 83-92. Cerca con Google

Wagner, J. M., and Karnitz, L. M. (2009). Cisplatin-induced DNA damage activates replication checkpoint signaling components that differentially affect tumor cell survival. Mol Pharmacol 76, 208-214. Cerca con Google

Wang, S., Zhang, M., Liang, B., Xu, J., Xie, Z., Liu, C., Viollet, B., Yan, D., and Zou, M. H. (2010a). AMPKalpha2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes. Circ Res 106, 1117-1128. Cerca con Google

Wang, T., Nelson, R. A., Bogardus, A., and Grannis, F. W., Jr. (2010b). Five-year lung cancer survival: which advanced stage nonsmall cell lung cancer patients attain long-term survival? Cancer 116, 1518-1525. Cerca con Google

Waris, G., and Ahsan, H. (2006). Reactive oxygen species: role in the development of cancer and various chronic conditions. J Carcinog 5, 14. Cerca con Google

Watson, J. (2013). Oxidants, antioxidants and the current incurability of metastatic cancers. Open Biol 3, 120144. Cerca con Google

Weinberg, F., Hamanaka, R., Wheaton, W. W., Weinberg, S., Joseph, J., Lopez, M., Kalyanaraman, B., Mutlu, G. M., Budinger, G. R., and Chandel, N. S. (2010). Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci U S A 107, 8788-8793. Cerca con Google

Wilkerson, M. D., Yin, X., Walter, V., Zhao, N., Cabanski, C. R., Hayward, M. C., Miller, C. R., Socinski, M. A., Parsons, A. M., Thorne, L. B., et al. (2012). Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation. PLoS One 7, e36530. Cerca con Google

Wingo, S. N., Gallardo, T. D., Akbay, E. A., Liang, M. C., Contreras, C. M., Boren, T., Shimamura, T., Miller, D. S., Sharpless, N. E., Bardeesy, N., et al. (2009). Somatic LKB1 mutations promote cervical cancer progression. PLoS One 4, e5137. Cerca con Google

Witters, L. A., Kemp, B. E., and Means, A. R. (2006). Chutes and Ladders: the search for protein kinases that act on AMPK. Trends Biochem Sci 31, 13-16. Cerca con Google

Woolley, J. F., Naughton, R., Stanicka, J., Gough, D. R., Bhatt, L., Dickinson, B. C., Chang, C. J., and Cotter, T. G. (2012). H2O2 production downstream of FLT3 is mediated by p22phox in the endoplasmic reticulum and is required for STAT5 signalling. PLoS One 7, e34050. Cerca con Google

Xie, Z., Dong, Y., Zhang, J., Scholz, R., Neumann, D., and Zou, M. H. (2009). Identification of the serine 307 of LKB1 as a novel phosphorylation site essential for its nucleocytoplasmic transport and endothelial cell angiogenesis. Mol Cell Biol 29, 3582-3596. Cerca con Google

Xu, H. G., Zhai, Y. X., Chen, J., Lu, Y., Wang, J. W., Quan, C. S., Zhao, R. X., Xiao, X., He, Q., Werle, K. D., et al. (2014). LKB1 reduces ROS-mediated cell damage via activation of p38. Oncogene. Cerca con Google

Yamada, E., and Bastie, C. C. (2014). Disruption of Fyn SH3 domain interaction with a proline-rich motif in liver kinase B1 results in activation of AMP-activated protein kinase. PLoS One 9, e89604. Cerca con Google

Yang, Z. J., Chee, C. E., Huang, S., and Sinicrope, F. A. (2011). The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther 10, 1533-1541. Cerca con Google

You, B. R., and Park, W. H. (2012). Arsenic trioxide induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion. Oncol Rep 28, 749-757. Cerca con Google

Zeqiraj, E., Filippi, B. M., Deak, M., Alessi, D. R., and van Aalten, D. M. (2009). Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. Science 326, 1707-1711. Cerca con Google

Zhan, Y. Y., Chen, Y., Zhang, Q., Zhuang, J. J., Tian, M., Chen, H. Z., Zhang, L. R., Zhang, H. K., He, J. P., Wang, W. J., et al. (2012). The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK. Nat Chem Biol 8, 897-904. Cerca con Google

Zhong, D., Guo, L., de Aguirre, I., Liu, X., Lamb, N., Sun, S. Y., Gal, A. A., Vertino, P. M., and Zhou, W. (2006). LKB1 mutation in large cell carcinoma of the lung. Lung Cancer 53, 285-294. Cerca con Google

Solo per lo Staff dell Archivio: Modifica questo record