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ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer

Oncogene volume 33, pages 1828–1839 (2014)Cite this article

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Abstract

The mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase (MEK/ERK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways are often concurrently activated by separate genetic alterations in colorectal cancer (CRC), which is associated with CRC progression and poor survival. However, how activating both pathways is required for CRC metastatic progression remains unclear. Our recent study showed that both ERK and AKT signaling are required to activate eukaryotic translation initiation factor 4E (eIF4E)-initiated cap-dependent translation via convergent regulation of the translational repressor 4E-binding protein 1 (4E-BP1) for maintaining CRC transformation. Here, we identified that the activation of cap-dependent translation by cooperative ERK and AKT signaling is critical for promotion of CRC motility and metastasis. In CRC cells with coexistent mutational activation of ERK and AKT pathways, inhibition of either MEK or AKT alone showed limited activity in inhibiting cell migration and invasion, but combined inhibition resulted in profound effects. Genetic blockade of the translation initiation complex by eIF4E knockdown or expression of a dominant active 4E-BP1 mutant effectively inhibited migration, invasion and metastasis of CRC cells, whereas overexpression of eIF4E or knockdown of 4E-BP1 had the opposite effect and markedly reduced their dependence on ERK and AKT signaling for cell motility. Mechanistically, we found that these effects were largely dependent on the increase in mammalian target of rapamycin complex 1 (mTORC1)-mediated survivin translation by ERK and AKT signaling. Despite the modest effect of survivin knockdown on tumor growth, reduction of the translationally regulated survivin profoundly inhibited motility and metastasis of CRC. These findings reveal a critical mechanism underlying the translational regulation of CRC metastatic progression, and suggest that targeting cap-dependent translation may provide a promising treatment strategy for advanced CRC.

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Abbreviations

4E-BP1:

4E-binding protein 1

CRC:

colorectal cancer

DMSO:

dimethyl sulfoxide

eIF4E:

eukaryotic translation initiation factor 4E

ERK:

extracellular signal-regulated kinase

MEK:

mitogen-activated extracellular signal-regulated kinase

mTOR:

mammalian target of rapamycin

mTORC1:

mammalian target of rapamycin complex 1

PI3K:

phosphatidylinositol 3-kinase

PIK3CA:

p110α catalytic subunit of PI3K

UTR:

untranslated region.

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.

    Article  Google Scholar 

  2. Chu E . An update on the current and emerging targeted agents in metastatic colorectal cancer. Clin Colorectal Cancer 2012; 11: 1–13.

    Article  CAS  Google Scholar 

  3. Sebolt-Leopold JS, Herrera R . Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 2004; 4: 937–947.

    Article  CAS  Google Scholar 

  4. Cancer Genome Atlas Research Network, Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487: 330–337.

    Article  Google Scholar 

  5. Parsons DW, Wang TL, Samuels Y, Bardelli A, Cummins JM, DeLong L et al. Colorectal cancer: mutations in a signalling pathway. Nature 2005; 436: 792.

    Article  CAS  Google Scholar 

  6. Wee S, Jagani Z, Xiang KX, Loo A, Dorsch M, Yao YM et al. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res 2009; 69: 4286–4293.

    Article  CAS  Google Scholar 

  7. Balmanno K, Chell SD, Gillings AS, Hayat S, Cook SJ . Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines. Int J Cancer 2009; 125: 2332–2341.

    Article  CAS  Google Scholar 

  8. She QB, Halilovic E, Ye Q, Zhen W, Shirasawa S, Sasazuki T et al. 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. Cancer Cell 2010; 18: 39–51.

    Article  CAS  Google Scholar 

  9. Halilovic E, She QB, Ye Q, Pagliarini R, Sellers WR, Solit DB et al. PIK3CA mutation uncouples tumor growth and cyclin D1 regulation from MEK/ERK and mutant KRAS signaling. Cancer Res 2010; 70: 6804–6814.

    Article  CAS  Google Scholar 

  10. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012; 483: 100–103.

    Article  CAS  Google Scholar 

  11. Sonenberg N, Hinnebusch AG . Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 2009; 136: 731–745.

    Article  CAS  Google Scholar 

  12. Mamane Y, Petroulakis E, Martineau Y, Sato TA, Larsson O, Rajasekhar VK et al. Epigenetic activation of a subset of mRNAs by eIF4E explains its effects on cell proliferation. PLoS One 2007; 2: e242.

    Article  Google Scholar 

  13. Livingstone M, Atas E, Meller A, Sonenberg N . Mechanisms governing the control of mRNA translation. Phys Biol 2010; 7: 021001.

    Article  Google Scholar 

  14. Silvera D, Formenti SC, Schneider RJ . Translational control in cancer. Nat Rev Cancer 2010; 10: 254–266.

    Article  CAS  Google Scholar 

  15. Rosenwald IB, Chen JJ, Wang S, Savas L, London IM, Pullman J . Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. Oncogene 1999; 18: 2507–2517.

    Article  CAS  Google Scholar 

  16. Berkel HJ, Turbat-Herrera EA, Shi R, de Benedetti A . Expression of the translation initiation factor eIF4E in the polyp-cancer sequence in the colon. Cancer Epidemiol Biomarkers Prev 2001; 10: 663–666.

    CAS  PubMed  Google Scholar 

  17. Martin ME, Perez MI, Redondo C, Alvarez MI, Salinas M, Fando JL . 4E binding protein 1 expression is inversely correlated to the progression of gastrointestinal cancers. Int J Biochem Cell Biol 2000; 32: 633–642.

    Article  CAS  Google Scholar 

  18. Armengol G, Rojo F, Castellvi J, Iglesias C, Cuatrecasas M, Pons B et al. 4E-binding protein 1: a key molecular ‘funnel factor’ in human cancer with clinical implications. Cancer Res 2007; 67: 7551–7555.

    Article  CAS  Google Scholar 

  19. Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol 2011; 29: 4688–4695.

    Article  CAS  Google Scholar 

  20. Hanrahan AJ, Schultz N, Westfal ML, Sakr RA, Giri DD, Scarperi S et al. Genomic complexity and AKT dependence in serous ovarian cancer. Cancer Discov 2012; 2: 56–67.

    Article  CAS  Google Scholar 

  21. Altieri DC . Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 2008; 8: 61–70.

    Article  CAS  Google Scholar 

  22. Mehrotra S, Languino LR, Raskett CM, Mercurio AM, Dohi T, Altieri DC . IAP regulation of metastasis. Cancer Cell 2010; 17: 53–64.

    Article  CAS  Google Scholar 

  23. McKenzie JA, Liu T, Goodson AG, Grossman D . Survivin enhances motility of melanoma cells by supporting Akt activation and alpha 5 integrin upregulation. Cancer Res 2010; 70: 7927–7937.

    Article  CAS  Google Scholar 

  24. Zhang M, Coen JJ, Suzuki Y, Siedow MR, Niemierko A, Khor LY et al. Survivin is a potential mediator of prostate cancer metastasis. Int J Radiat Oncol Biol Phys 2010; 78: 1095–1103.

    Article  CAS  Google Scholar 

  25. Chu XY, Chen LB, Wang JH, Su QS, Yang JR, Lin Y et al. Overexpression of survivin is correlated with increased invasion and metastasis of colorectal cancer. J Surg Oncol 2012; 105: 520–528.

    Article  CAS  Google Scholar 

  26. Zoncu R, Efeyan A, Sabatini DM . mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011; 12: 21–35.

    Article  CAS  Google Scholar 

  27. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC . Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002; 10: 151–162.

    Article  CAS  Google Scholar 

  28. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP . Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005; 121: 179–193.

    Article  CAS  Google Scholar 

  29. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009; 7: e38.

    Article  Google Scholar 

  30. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 2009; 284: 8023–8032.

    Article  CAS  Google Scholar 

  31. Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res 2010; 70: 288–298.

    Article  CAS  Google Scholar 

  32. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110: 163–175.

    Article  CAS  Google Scholar 

  33. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM . Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science 2005; 307: 1098–1101.

    Article  CAS  Google Scholar 

  34. Dilling MB, Germain GS, Dudkin L, Jayaraman AL, Zhang X, Harwood FC et al. 4E-binding proteins, the suppressors of eukaryotic initiation factor 4E, are down-regulated in cells with acquired or intrinsic resistance to rapamycin. J Biol Chem 2002; 277: 13907–13917.

    Article  CAS  Google Scholar 

  35. Ilic N, Utermark T, Widlund HR, Roberts TM . PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis. Proc Natl Acad Sci USA 2011; 108: E699–E708.

    Article  CAS  Google Scholar 

  36. Zindy P, Berge Y, Allal B, Filleron T, Pierredon S, Cammas A et al. Formation of the eIF4F translation–initiation complex determines sensitivity to anticancer drugs targeting the EGFR and HER2 receptors. Cancer Res 2011; 71: 4068–4073.

    Article  CAS  Google Scholar 

  37. Nguyen DX, Massague J . Genetic determinants of cancer metastasis. Nat Rev Genet 2007; 8: 341–352.

    Article  CAS  Google Scholar 

  38. Schwanhausser B, Busse D, Li N, Dittmar G, Schuchhardt J, Wolf J et al. Global quantification of mammalian gene expression control. Nature 2011; 473: 337–342.

    Article  Google Scholar 

  39. Hernandez JM, Farma JM, Coppola D, Hakam A, Fulp WJ, Chen DT et al. Expression of the antiapoptotic protein survivin in colon cancer. Clin Colorectal Cancer 2011; 10: 188–193.

    Article  Google Scholar 

  40. Mamane Y, Petroulakis E, LeBacquer O, Sonenberg N . mTOR, translation initiation and cancer. Oncogene 2006; 25: 6416–6422.

    Article  CAS  Google Scholar 

  41. Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res 2011; 71: 3246–3256.

    Article  CAS  Google Scholar 

  42. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 2012; 485: 55–61.

    Article  CAS  Google Scholar 

  43. Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 2005; 65: 7052–7058.

    Article  CAS  Google Scholar 

  44. O’Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66: 1500–1508.

    Article  Google Scholar 

  45. Mazzoletti M, Bortolin F, Brunelli L, Pastorelli R, Di Giandomenico S, Erba E et al. Combination of PI3K/mTOR inhibitors: antitumor activity and molecular correlates. Cancer Res 2011; 71: 4573–4584.

    Article  CAS  Google Scholar 

  46. Thomas HE, Mercer CA, Carnevalli LS, Park J, Andersen JB, Conner EA et al. mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma. Sci Transl Med 2012; 4: 139ra184.

    Article  Google Scholar 

  47. Floc'h N, Kinkade CW, Kobayashi T, Aytes A, Lefebvre C, Mitrofanova A et al. Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model. Cancer Res 2012; 72: 4483–4493.

    Article  CAS  Google Scholar 

  48. Moroz E, Carlin S, Dyomina K, Burke S, Thaler HT, Blasberg R et al. Real-time imaging of HIF-1alpha stabilization and degradation. PLoS One 2009; 4: e5077.

    Article  Google Scholar 

  49. Pause A, Belsham GJ, Gingras AC, Donze O, Lin TA, Lawrence JC et al. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function. Nature 1994; 371: 762–767.

    Article  CAS  Google Scholar 

  50. Zaytseva YY, Rychahou PG, Gulhati P, Elliott VA, Mustain WC, O’Connor K et al. Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Res 2012; 72: 1504–1517.

    Article  CAS  Google Scholar 

  51. She QB, Chandarlapaty S, Ye Q, Lobo J, Haskell KM, Leander KR et al. Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. PLoS One 2008; 3: e3065.

    Article  Google Scholar 

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Acknowledgements

We thank Drs Rina Plattner and Kathleen O’Connor and Ms Donna Gilbreath for critical reading and editing of this manuscript, Dr Ronald Blasberg for providing the SFG-FLuc-IRES2-GFP construct. Dr Piotr Rychahou for the assistance in the animal experiments, and Ms Dana Napier for the histologic tissue processing. This work was supported by grants from NCI (R01CA175105 to Q-B She, P30CA147886 and Gastrointestinal Cancer SPORE P20CA150343 to BM Evers), ACS (IRG85-001-22 to Q-B She), NIH/NCATS UL1RR033173 (KL2RR0033171 to Q-B She), and the Markey Cancer Center Start-up fund (to Q-B She).

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  1. Q Ye and W Cai: The first two authors contributed equally to this work.

Authors and Affiliations

  1. Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA

    Q Ye, W Cai, Y Zheng, B M Evers & Q-B She

  2. Department of Molecular and Biomedical Pharmacology, College of Medicine, University of Kentucky, Lexington, KY, USA

    Q Ye, W Cai, Y Zheng & Q-B She

  3. Department of Surgery, College of Medicine, University of Kentucky, Lexington, KY, USA

    B M Evers

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Correspondence to Q-B She.

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Ye, Q., Cai, W., Zheng, Y. et al. ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer. Oncogene 33, 1828–1839 (2014). https://doi.org/10.1038/onc.2013.122

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