Article Contents
- 2023 (Vol.86)
- 2022 (Vol.85)
- 2021 (Vol.84)
- 2020 (Vol.83)
- 2019 (Vol.82)
- 2018 (Vol.81)
- 2017 (Vol.80)
- 2016 (Vol.79)
- 2015 (Vol.78)
- 2014 (Vol.76)
- 2013 (Vol.74)
- 2012 (Vol.72)
- 2011 (Vol.70)
- 2010 (Vol.68)
- 2009 (Vol.66)
- 2008 (Vol.64)
- 2007 (Vol.62)
- 2006 (Vol.60)
- 2005 (Vol.58)
- 2004 (Vol.56)
- 2003 (Vol.54)
- 2002 (Vol.52)
Autophagy Inhibition with Monensin Enhances Cell Cycle Arrest and Apoptosis Induced by mTOR or Epidermal Growth Factor Receptor Inhibitors in Lung Cancer Cells
Eun-Hui Jeong (Korea Cancer Center Hospital)
Tae-Gul Lee (Korea Cancer Center Hospital)
Seo Yun Kim (Korea Cancer Center Hospital)
Hye-Ryoun Kim (Korea Cancer Center Hospital)
Cheol Hyeon Kim (Korea Cancer Center Hospital)
- Downloaded
- Viewed
Abstract
Background: In cancer cells, autophagy is generally induced as a pro-survival mechanism in response to treatment-associated genotoxic and metabolic stress. Thus, concurrent autophagy inhibition can be expected to have a synergistic effect with chemotherapy on cancer cell death. Monensin, a polyether antibiotic, is known as an autophagy inhibitor, which interferes with the fusion of autophagosome and lysosome. There have been a few reports of its effect in combination with anticancer drugs. We performed this study to investigate whether erlotinib, an epidermal growth factor receptor inhibitor, or rapamycin, an mammalian target of rapamycin (mTOR) inhibitor, is effective in combination therapy with monensin in non-small cell lung cancer cells. Methods: NCI-H1299 cells were treated with rapamycin or erlotinib, with or without monensin pretreatment, and then subjected to growth inhibition assay, apoptosis analysis by flow cytometry, and cell cycle analysis on the basis of the DNA contents histogram. Finally, a Western blot analysis was done to examine the changes of proteins related to apoptosis and cell cycle control. Results: Monensin synergistically increases growth inhibition and apoptosis induced by rapamycin or erlotinib. The number of cells in the sub-G1 phase increases noticeably after the combination treatment. Increase of proapoptotic proteins, including bax, cleaved caspase 3, and cleaved poly(ADP-ribose) polymerase, and decrease of anti-apoptotic proteins, bcl-2 and bcl-xL, are augmented by the combination treatment with monensin. The promoters of cell cycle progression, notch3 and skp2, decrease and p21, a cyclin-dependent kinase inhibitor, accumulates within the cell during this process. Conclusion: Our findings suggest that concurrent autophagy inhibition could have a role in lung cancer treatment.
- keywords
- Autophagy, Apoptosis, Cell Cycle, Monensin, Epidermal Growth Factor Receptor-Neu Receptor, TOR Serine-Threonine Kinases
Reference
Marx J. Autophagy: is it cancer’s friend or foe? Science 2006; 312:1160-1.
Hippert MM, O’Toole PS, Thorburn A. Autophagy in cancer: good, bad, or both? Cancer Res 2006;66:9349-51.
Turcotte S, Giaccia AJ. Targeting cancer cells through autophagy for anticancer therapy. Curr Opin Cell Biol 2010;22:246- 51.
Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 2005;5:726-34.
Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, et al. Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol 2005;25:1025-40.
Huczynski A, Stefanska J, Przybylski P, Brzezinski B, Bartl F. Synthesis and antimicrobial properties of monensin A esters. Bioorg Med Chem Lett 2008;18:2585-9.
Hirsch FR, Scagliotti GV, Langer CJ, Varella-Garcia M, Franklin WA. Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies. Lung Cancer 2003;41 Suppl 1:S29-42.
Scagliotti GV, Selvaggi G, Novello S, Hirsch FR. The biology of epidermal growth factor receptor in lung cancer. Clin Cancer Res 2004;10(12 Pt 2):4227s-32s.
Han W, Pan H, Chen Y, Sun J, Wang Y, Li J, et al. EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells. PLoS One 2011;6:e18691.
Takezawa K, Okamoto I, Tanizaki J, Kuwata K, Yamaguchi H, Fukuoka M, et al. Enhanced anticancer effect of the combination of BIBW2992 and thymidylate synthase-targeted agents in non-small cell lung cancer with the T790M mutation of epidermal growth factor receptor. Mol Cancer Ther 2010;9:1647-56.
Sos ML, Rode HB, Heynck S, Peifer M, Fischer F, Kluter S, et al. Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation. Cancer Res 2010;70:868-74.
Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 2009;27:2278-87.
Zou ZQ, Zhang XH, Wang F, Shen QJ, Xu J, Zhang LN, et al. A novel dual PI3Kalpha/mTOR inhibitor PI-103 with high antitumor activity in non-small cell lung cancer cells. Int J Mol Med 2009;24:97-101.
Sheppard K, Kinross KM, Solomon B, Pearson RB, Phillips WA. Targeting PI3 kinase/AKT/mTOR signaling in cancer. Crit Rev Oncog 2012;17:69-95.
Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer 2007;7:961-7.
Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006;10:51-64.
Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007;117:326-36.
Amaravadi RK, Lippincott-Schwartz J, Yin XM, Weiss WA, Takebe N, Timmer W, et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res 2011;17:654-66.
Svensson JP, Fry RC, Wang E, Somoza LA, Samson LD. Identification of novel human damage response proteins targeted through yeast orthology. PLoS One 2012;7:e37368.
Hou W, Han J, Lu C, Goldstein LA, Rabinowich H. Autophagic degradation of active caspase-8: a crosstalk mechanism between autophagy and apoptosis. Autophagy 2010;6:891-900.
Li X, Lu Y, Pan T, Fan Z. Roles of autophagy in cetuximab-mediated cancer therapy against EGFR. Autophagy 2010;6:1066- 77.
Wu YT, Tan HL, Shui G, Bauvy C, Huang Q, Wenk MR, et al. Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J Biol Chem 2010;285:10850-61.
Powis G, Bonjouklian R, Berggren MM, Gallegos A, Abraham R, Ashendel C, et al. Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res 1994;54:2419-23.
Blommaart EF, Krause U, Schellens JP, Vreeling-Sindelarova H, Meijer AJ. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem 1997;243:240-6.
Kaini RR, Hu CA. Synergistic killing effect of chloroquine and androgen deprivation in LNCaP cells. Biochem Biophys Res Commun 2012;425:150-6.
Rahim R, Strobl JS. Hydroxychloroquine, chloroquine, and alltrans retinoic acid regulate growth, survival, and histone acetylation in breast cancer cells. Anticancer Drugs 2009;20:736- 45.
Klionsky DJ, Elazar Z, Seglen PO, Rubinsztein DC. Does bafilomycin A1 block the fusion of autophagosomes with lysosomes? Autophagy 2008;4:849-950.
Swampillai AL, Salomoni P, Short SC. The role of autophagy in clinical practice. Clin Oncol (R Coll Radiol) 2012;24:387- 95.
Butaye P, Devriese LA, Haesebrouck F. Antimicrobial growth promoters used in animal feed: effects of less well known antibiotics on gram-positive bacteria. Clin Microbiol Rev 2003;16:175-88.
Ketola K, Vainio P, Fey V, Kallioniemi O, Iljin K. Monensin is a potent inducer of oxidative stress and inhibitor of androgen signaling leading to apoptosis in prostate cancer cells. Mol Cancer Ther 2010;9:3175-85.
- Downloaded
- Viewed
- 0KCI Citations
- 0WOS Citations