Myc-Driven Overgrowth Requires Unfolded Protein Response-Mediated Induction of Autophagy and Antioxidant Responses in

English version České info

Autophagy, a lysosomal self-degradation and recycling pathway, plays dual roles in tumorigenesis. Autophagy deficiency predisposes to cancer, at least in part, through accumulation of the selective autophagy cargo p62, leading to activation of antioxidant responses and tumor formation. While cell growth and autophagy are inversely regulated in most cells, elevated levels of autophagy are observed in many established tumors, presumably mediating survival of cancer cells. Still, the relationship of autophagy and oncogenic signaling is poorly characterized. Here we show that the evolutionarily conserved transcription factor Myc (dm), a proto-oncogene involved in cell growth and proliferation, is also a physiological regulator of autophagy in Drosophila melanogaster. Loss of Myc activity in null mutants or in somatic clones of cells inhibits autophagy. Forced expression of Myc results in cell-autonomous increases in cell growth, autophagy induction, and p62 (Ref2P)-mediated activation of Nrf2 (cnc), a transcription factor promoting antioxidant responses. Mechanistically, Myc overexpression increases unfolded protein response (UPR), which leads to PERK-dependent autophagy induction and may be responsible for p62 accumulation. Genetic or pharmacological inhibition of UPR, autophagy or p62/Nrf2 signaling prevents Myc-induced overgrowth, while these pathways are dispensable for proper growth of control cells. In addition, we show that the autophagy and antioxidant pathways are required in parallel for excess cell growth driven by Myc. Deregulated expression of Myc drives tumor progression in most human cancers, and UPR and autophagy have been implicated in the survival of Myc-dependent cancer cells. Our data obtained in a complete animal show that UPR, autophagy and p62/Nrf2 signaling are required for Myc-dependent cell growth. These novel results give additional support for finding future approaches to specifically inhibit the growth of cancer cells addicted to oncogenic Myc.

Vyšlo v časopise: Myc-Driven Overgrowth Requires Unfolded Protein Response-Mediated Induction of Autophagy and Antioxidant Responses in. PLoS Genet 9(8): e32767. doi:10.1371/journal.pgen.1003664
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003664

Souhrn

Zdroje

1. NeufeldTP (2010) TOR-dependent control of autophagy: biting the hand that feeds. Curr Opin Cell Biol 22 : 157–168.

2. ScottRC, JuhaszG, NeufeldTP (2007) Direct induction of autophagy by atg1 inhibits cell growth and induces apoptotic cell death. Curr Biol 17 : 1–11.

3. HosokawaN, HaraY, MizushimaN (2007) Generation of cell lines with tetracycline-regulated autophagy and a role for autophagy in controlling cell size. FEBS Lett 581 : 2623–2629.

4. JuhaszG, ErdiB, SassM, NeufeldTP (2007) Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes Dev 21 : 3061–3066.

5. SimonsenA, CummingRC, BrechA, IsaksonP, SchubertDR, et al. (2008) Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy 4 : 176–184.

6. MizushimaN, LevineB, CuervoAM, KlionskyDJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451 : 1069–1075.

7. WhiteE (2012) Deconvoluting the context-dependent role for autophagy in cancer. Nature Rev Cancer 12 : 401–410.

8. CheongH, LuC, LindstenT, ThompsonCB (2012) Therapeutic targets in cancer cell metabolism and autophagy. Nat Biotechnol 30 : 671–678.

9. EilersM, EisenmanRN (2008) Myc's broad reach. Genes Dev 22 : 2755–2766.

10. LittlewoodTD, KreuzalerP, EvanGI (2012) All things to all people. Cell 151 : 11–13.

11. SoucekL, EvanGI (2010) The ups and downs of Myc biology. Curr Opin Genet Dev 20 : 91–95.

12. Weinberg RA (2007) The Biology of Cancer. New York: Garland Science.

13. JohnstonLA, ProberDA, EdgarBA, EisenmanRN, GallantP (1999) Drosophila myc regulates cellular growth during development. Cell 98 : 779–790.

14. PierceSB, YostC, BrittonJS, LooLW, FlynnEM, et al. (2004) dMyc is required for larval growth and endoreplication in Drosophila. Development 131 : 2317–2327.

15. JuhaszG, HillJH, YanY, SassM, BaehreckeEH, et al. (2008) The class III PI(3)K Vps34 promotes autophagy and endocytosis but not TOR signaling in Drosophila. J Cell Biol 181 : 655–666.

16. KlionskyDJ, AbdallaFC, AbeliovichH, AbrahamRT, Acevedo-ArozenaA, et al. (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8 : 445–544.

17. PircsK, NagyP, VargaA, VenkeiZ, ErdiB, et al. (2012) Advantages and limitations of different p62-based assays for estimating autophagic activity in Drosophila. PloS one 7: e44214.

18. ScottRC, SchuldinerO, NeufeldTP (2004) Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev Cell 7 : 167–178.

19. TakatsS, NagyP, VargaA, PircsK, KarpatiM, et al. (2013) Autophagosomal Syntaxin17-dependent lysosomal degradation maintains neuronal function in Drosophila. J Cell Biol 201 : 531–539.

20. BarthJM, SzabadJ, HafenE, KohlerK (2011) Autophagy in Drosophila ovaries is induced by starvation and is required for oogenesis. Cell Death Differ 18 : 915–924.

21. NezisIP, SimonsenA, SagonaAP, FinleyK, GaumerS, et al. (2008) Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain. J Cell Biol 180 : 1065–1071.

22. SaucedoLJ, EdgarBA (2002) Why size matters: altering cell size. Curr Opin Genet Dev 12 : 565–571.

23. ChangYY, NeufeldTP (2009) An Atg1/Atg13 complex with multiple roles in TOR-mediated autophagy regulation. Mol Biol Cell 20 : 2004–2014.

24. MizushimaN, YoshimoriT (2007) How to interpret LC3 immunoblotting. Autophagy 3 : 542–545.

25. NezisIP, ShravageBV, SagonaAP, LamarkT, BjorkoyG, et al. (2010) Autophagic degradation of dBruce controls DNA fragmentation in nurse cells during late Drosophila melanogaster oogenesis. J Cell Biol 190 : 523–531.

26. KimuraS, NodaT, YoshimoriT (2007) Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3 : 452–460.

27. RintelenF, StockerH, ThomasG, HafenE (2001) PDK1 regulates growth through Akt and S6K in Drosophila. Proc Natl Acad Sci USA 98 : 15020–15025.

28. MoscatJ, Diaz-MecoMT (2012) p62: a versatile multitasker takes on cancer. Trends Biochem Sci 37 : 230–236.

29. MathewR, KarpCM, BeaudoinB, VuongN, ChenG, et al. (2009) Autophagy suppresses tumorigenesis through elimination of p62. Cell 137 : 1062–1075.

30. InamiY, WaguriS, SakamotoA, KounoT, NakadaK, et al. (2011) Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J Cell Biol 193 : 275–284.

31. KomatsuM, KurokawaH, WaguriS, TaguchiK, KobayashiA, et al. (2010) The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 12 : 213–223.

32. TakamuraA, KomatsuM, HaraT, SakamotoA, KishiC, et al. (2011) Autophagy-deficient mice develop multiple liver tumors. Genes Dev 25 : 795–800.

33. JainA, LamarkT, SjottemE, LarsenKB, AwuhJA, et al. (2010) p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem 285 : 22576–22591.

34. LiuXD, KoS, XuY, FattahEA, XiangQ, et al. (2012) Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress. J Biol Chem 287 : 19687–19698.

35. MalzerE, DalyML, MoloneyA, SendallTJ, ThomasSE, et al. (2010) Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response. J Cell Sci 123 : 2892–2900.

36. SoneM, ZengX, LareseJ, RyooHD (2013) A modified UPR stress sensing system reveals a novel tissue distribution of IRE1/XBP1 activity during normal Drosophila development. Cell Stress Chaperones 18 : 307–319.

37. WangS, KaufmanRJ (2012) The impact of the unfolded protein response on human disease. J Cell Biol 197 : 857–867.

38. AmaravadiRK, YuD, LumJJ, BuiT, ChristophorouMA, et al. (2007) Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 117 : 326–336.

39. MacleanKH, DorseyFC, ClevelandJL, KastanMB (2008) Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J Clin Invest 118 : 79–88.

40. HartLS, CunninghamJT, DattaT, DeyS, TameireF, et al. (2012) ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. J Clin Invest 122 : 4621–4634.

41. LuoJ, SoliminiNL, ElledgeSJ (2009) Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136 : 823–837.

42. KumaA, HatanoM, MatsuiM, YamamotoA, NakayaH, et al. (2004) The role of autophagy during the early neonatal starvation period. Nature 432 : 1032–1036.

43. MizushimaN, KomatsuM (2011) Autophagy: renovation of cells and tissues. Cell 147 : 728–741.

44. KomatsuM, WaguriS, KoikeM, SouYS, UenoT, et al. (2007) Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131 : 1149–1163.

45. ChanK, LuR, ChangJC, KanYW (1996) NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc Natl Acad Sci USA 93 : 13943–13948.

46. IshiiT, ItohK, TakahashiS, SatoH, YanagawaT, et al. (2000) Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem 275 : 16023–16029.

47. HardingHP, ZengH, ZhangY, JungriesR, ChungP, et al. (2001) Diabetes mellitus and exocrine pancreatic dysfunction in perk−/ −⁠ mice reveals a role for translational control in secretory cell survival. Mol Cell 7 : 1153–1163.

48. Vega-StrombergT (2003) Chemotherapy-induced secondary malignancies. J Infus Nurs 26 : 353–361.

49. HijiyaN, NessKK, RibeiroRC, HudsonMM (2009) Acute leukemia as a secondary malignancy in children and adolescents: current findings and issues. Cancer 115 : 23–35.

50. SykiotisGP, BohmannD (2008) Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila. Dev Cell 14 : 76–85.