Oncogene-mediated tumor transformation sensitizes cells to autophagy induction

Gargini,Ricardo; García-Escudero,Vega; Izquierdo,Marta; Wandosell,Francisco

doi:10.3892/or.2016.4699

Oncogene-mediated tumor transformation sensitizes cells to autophagy induction

Authors:
- Ricardo Gargini
- Vega García-Escudero
- Marta Izquierdo
- Francisco Wandosell
View Affiliations

Affiliations: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autonoma de Madrid, 28049 Madrid, Spain
Published online on: March 23, 2016 https://doi.org/10.3892/or.2016.4699
Pages: 3689-3695

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The process of tumorigenesis induces alterations in numerous cellular pathways including the main eukaryotic metabolic routes. It has been recently demonstrated that autophagy is part of the oncogene-induced senescence phenotype although its role in tumor establishment has not been completely clarified. In the present study, we showed that non‑transformed cells are sensitized to mitochondrial stress and autophagy induction when they are transformed by oncogenes such as c-Myc or Ras. We observed that overexpression of c-Myc or Ras increased AMP-activated protein kinase (AMPK) phosphorylation and the expression of p62, a known partner for degradation by autophagy. The activation of AMPK was found to favor the activation of FoxO3 which was prevented by the inhibition of AMPK. The transcriptional activation mediated by FoxO3 upregulated genes such as BNIP3 and LC3. Finally, the transformation by oncogenes such as c-Myc and Ras predisposes tumor cells to autophagy induction as a consequence of mitochondrial stress and impairs tumor growth in vitro and in vivo, which may have therapeutic implications.

View Figures

View References

1	Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, Bray K, Reddy A, Bhanot G, Gelinas C, et al: Autophagy suppresses tumorigenesis through elimination of p62. Cell. 137:1062–1075. 2009. View Article : Google Scholar : PubMed/NCBI
2	Tang YC, Williams BR, Siegel JJ and Amon A: Identification of aneuploidy-selective antiproliferation compounds. Cell. 144:499–512. 2011. View Article : Google Scholar : PubMed/NCBI
3	Courtois-Cox S, Genther Williams SM, Reczek EE, Johnson BW, McGillicuddy LT, Johannessen CM, Hollstein PE, MacCollin M and Cichowski K: A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell. 10:459–472. 2006. View Article : Google Scholar : PubMed/NCBI
4	Young AR, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JF, Tavaré S, Arakawa S, Shimizu S, Watt FM, et al: Autophagy mediates the mitotic senescence transition. Genes Dev. 23:798–803. 2009. View Article : Google Scholar : PubMed/NCBI
5	Rong Y, McPhee CK, Deng S, Huang L, Chen L, Liu M, Tracy K, Baehrecke EH, Yu L and Lenardo MJ: Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation. Proc Natl Acad Sci USA. 108:7826–7831. 2011. View Article : Google Scholar : PubMed/NCBI
6	Narita M, Young AR, Arakawa S, Samarajiwa SA, Nakashima T, Yoshida S, Hong S, Berry LS, Reichelt S, Ferreira M, et al: Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science. 332:966–970. 2011. View Article : Google Scholar : PubMed/NCBI
7	Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemons JM, Karantza V, et al: Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 25:460–470. 2011. View Article : Google Scholar : PubMed/NCBI
8	Flier JS, Mueckler MM, Usher P and Lodish HF: Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science. 235:1492–1495. 1987. View Article : Google Scholar : PubMed/NCBI
9	Greer EL, Oskoui PR, Banko MR, Maniar JM, Gygi MP, Gygi SP and Brunet A: The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem. 282:30107–30119. 2007. View Article : Google Scholar : PubMed/NCBI
10	García-Escudero V and Gargini R: Autophagy induction as an efficient strategy to eradicate tumors. Autophagy. 4:923–925. 2008. View Article : Google Scholar : PubMed/NCBI
11	Gargini R, García-Escudero V and Izquierdo M: Therapy mediated by mitophagy abrogates tumor progression. Autophagy. 7:466–476. 2011. View Article : Google Scholar : PubMed/NCBI
12	Nikiforov MA, Riblett M, Tang WH, Gratchouck V, Zhuang D, Fernandez Y, Verhaegen M, Varambally S, Chinnaiyan AM, Jakubowiak AJ, et al: Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition. Proc Natl Acad Sci USA. 104:19488–19493. 2007. View Article : Google Scholar : PubMed/NCBI
13	Beauséjour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P and Campisi J: Reversal of human cellular senescence: Roles of the p53 and p16 pathways. EMBO J. 22:4212–4222. 2003. View Article : Google Scholar : PubMed/NCBI
14	Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, Thomas-Tikhonenko A and Thompson CB: Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest. 117:326–336. 2007. View Article : Google Scholar : PubMed/NCBI
15	Thibodeaux CA, Liu X, Disbrow GL, Zhang Y, Rone JD, Haddad BR and Schlegel R: Immortalization and transformation of human mammary epithelial cells by a tumor-derived Myc mutant. Breast Cancer Res Treat. 116:281–294. 2009. View Article : Google Scholar
16	Datta S, Hoenerhoff MJ, Bommi P, Sainger R, Guo WJ, Dimri M, Band H, Band V, Green JE and Dimri GP: Bmi-1 cooperates with H-Ras to transform human mammary epithelial cells via dysregulation of multiple growth-regulatory pathways. Cancer Res. 67:10286–10295. 2007. View Article : Google Scholar : PubMed/NCBI
17	Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Øvervatn A, Bjørkøy G and Johansen T: p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 282:24131–24145. 2007. View Article : Google Scholar : PubMed/NCBI
18	Duran A, Linares JF, Galvez AS, Wikenheiser K, Flores JM, Diaz-Meco MT and Moscat J: The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell. 13:343–354. 2008. View Article : Google Scholar : PubMed/NCBI
19	Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J, et al: FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 6:458–471. 2007. View Article : Google Scholar : PubMed/NCBI
20	Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, Lecker SH and Goldberg AL: FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 6:472–483. 2007. View Article : Google Scholar : PubMed/NCBI
21	Maclean KH, Dorsey FC, Cleveland JL and Kastan MB: Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J Clin Invest. 118:79–88. 2008. View Article : Google Scholar
22	Kanzawa T, Zhang L, Xiao L, Germano IM, Kondo Y and Kondo S: Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. Oncogene. 24:980–991. 2005. View Article : Google Scholar
23	Chang CP, Yang MC, Liu HS, Lin YS and Lei HY: Concanavalin A induces autophagy in hepatoma cells and has a therapeutic effect in a murine in situ hepatoma model. Hepatology. 45:286–296. 2007. View Article : Google Scholar : PubMed/NCBI
24	García-Escudero V, Gargini R and Izquierdo M: Glioma regression in vitro and in vivo by a suicide combined treatment. Mol Cancer Res. 6:407–417. 2008. View Article : Google Scholar : PubMed/NCBI
25	Kim H, Farris J, Christman SA, Kong BW, Foster LK, O'Grady SM and Foster DN: Events in the immortalizing process of primary human mammary epithelial cells by the catalytic subunit of human telomerase. Biochem J. 365:765–772. 2002. View Article : Google Scholar : PubMed/NCBI
26	Levine AJ and Puzio-Kuter AM: The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science. 330:1340–1344. 2010. View Article : Google Scholar : PubMed/NCBI
27	Jeon SM, Chandel NS and Hay N: AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature. 485:661–665. 2012. View Article : Google Scholar : PubMed/NCBI
28	Dang CV: Links between metabolism and cancer. Genes Dev. 26:877–890. 2012. View Article : Google Scholar : PubMed/NCBI
29	Lin A, Yao J, Zhuang L, Wang D, Han J, Lam EW and Gan B: The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress. Oncogene. 33:3183–3194. 2014. View Article : Google Scholar
30	Yogalingam G and Pendergast AM: Abl kinases regulate autophagy by promoting the trafficking and function of lysosomal components. J Biol Chem. 283:35941–35953. 2008. View Article : Google Scholar : PubMed/NCBI
31	Turcotte S, Chan DA, Sutphin PD, Hay MP, Denny WA and Giaccia AJ: A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer Cell. 14:90–102. 2008. View Article : Google Scholar : PubMed/NCBI
32	Weihua Z, Tsan R, Huang WC, Wu Q, Chiu CH, Fidler IJ and Hung MC: Survival of cancer cells is maintained by EGFR independent of its kinase activity. Cancer Cell. 13:385–393. 2008. View Article : Google Scholar : PubMed/NCBI
33	Lu Z, Luo RZ, Lu Y, Zhang X, Yu Q, Khare S, Kondo S, Kondo Y, Yu Y, Mills GB, et al: The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J Clin Invest. 118:3917–3929. 2008.PubMed/NCBI