Skip to main content

Advertisement

SpringerLink
Log in

Alternative splicing of S6K1 promotes non-small cell lung cancer survival

  • Original Article
  • Published:
Tumor Biology

Abstract

Ribosomal S6 kinase 1 (S6K1) that acts downstream of the mammalian target of rapamycin (mTOR) plays an important role in cell proliferation, protein translation, and cell survival. The gene RPS6KB1 encoding for S6K1 had been found to be alternatively spliced to form different isoforms. In this study, we identified that short isoforms of S6K1 splice variant were overproduced in non-small cell lung cancer (NSCLC). Moreover, suppression of S6K1 short isoforms inhibited NSCLC cell growth and induced apoptosis via upregulation of the BH3-only protein Bim in vitro and in vivo. Additionally, short isoforms of S6K1 activated mTORC1, leading to increased 4E-BP1 phosphorylation. Taken together, our findings suggested that S6K1 short isoforms were deregulated in NSCLC and promoted cell survival. Altogether, our study opens possibilities of new therapeutic approaches for NSCLC that selectively downregulate S6K1 shorter isoforms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. David CJ, Manley JL. Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev. 2010;24(21):2343–64. doi:10.1101/gad.1973010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Oltean S, Bates DO. Hallmarks of alternative splicing in cancer. Oncogene. 2014;33(46):5311–8. doi:10.1038/onc.2013.533.

    Article  CAS  PubMed  Google Scholar 

  3. Biamonti G, Catillo M, Pignataro D, Montecucco A, Ghigna C. The alternative splicing side of cancer. Semin Cell Dev Biol. 2014;32:30–6. doi:10.1016/j.semcdb.2014.03.016.

    Article  CAS  PubMed  Google Scholar 

  4. Venables JP, Klinck R, Koh C, Gervais-Bird J, Bramard A, Inkel L, et al. Cancer-associated regulation of alternative splicing. Nat Struct Mol Biol. 2009;16(6):670–6. doi:10.1038/nsmb.1608.

    Article  CAS  PubMed  Google Scholar 

  5. Kim E, Goren A, Ast G. Insights into the connection between cancer and alternative splicing. Trends Genet. 2008;24(1):7–10. doi:10.1016/j.tig.2007.10.001.

    Article  CAS  PubMed  Google Scholar 

  6. Venables JP. Unbalanced alternative splicing and its significance in cancer. Bioessays. 2006;28(4):378–86. doi:10.1002/bies.20390.

    Article  CAS  PubMed  Google Scholar 

  7. Singh RK, Cooper TA. Pre-mRNA splicing in disease and therapeutics. Trends Mol Med. 2012;18(8):472–82. doi:10.1016/j.molmed.2012.06.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–93. doi:10.1016/j.cell.2012.03.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1):21–35. doi:10.1038/nrm3025.

    Article  CAS  PubMed  Google Scholar 

  10. Ohanna M, Sobering AK, Lapointe T, Lorenzo L, Praud C, Petroulakis E, et al. Atrophy of S6K1(−/−) skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control. Nat Cell Biol. 2005;7(3):286–94. doi:10.1038/ncb1231.

    Article  CAS  PubMed  Google Scholar 

  11. Hsieh AC, Costa M, Zollo O, Davis C, Feldman ME, Testa JR, et al. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell. 2010;17(3):249–61. doi:10.1016/j.ccr.2010.01.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Maruani DM, Spiegel TN, Harris EN, Shachter AS, Unger HA, Herrero-Gonzalez S, et al. Estrogenic regulation of S6K1 expression creates a positive regulatory loop in control of breast cancer cell proliferation. Oncogene. 2012;31(49):5073–80. doi:10.1038/onc.2011.657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yamnik RL, Digilova A, Davis DC, Brodt ZN, Murphy CJ, Holz MK. S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. J Biol Chem. 2009;284(10):6361–9. doi:10.1074/jbc.M807532200.

    Article  CAS  PubMed  Google Scholar 

  14. Panwalkar A, Verstovsek S, Giles FJ. Mammalian target of rapamycin inhibition as therapy for hematologic malignancies. Cancer. 2004;100(4):657–66. doi:10.1002/cncr.20026.

    Article  CAS  PubMed  Google Scholar 

  15. Eyre TA, Collins GP, Goldstone AH, Cwynarski K. Time now to TORC the TORC? New developments in mTOR pathway inhibition in lymphoid malignancies. Br J Haematol. 2014;166(3):336–51. doi:10.1111/bjh.12945.

    Article  CAS  PubMed  Google Scholar 

  16. Bepler G, Koehler A. Multiple chromosomal aberrations and 11p allelotyping in lung cancer cell lines. Cancer Genet Cytogenet. 1995;84(1):39–45.

    Article  CAS  PubMed  Google Scholar 

  17. Monni O, Barlund M, Mousses S, Kononen J, Sauter G, Heiskanen M, et al. Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer. Proc Natl Acad Sci U S A. 2001;98(10):5711–6. doi:10.1073/pnas.091582298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D, Krainer AR. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol. 2007;14(3):185–93. doi:10.1038/nsmb1209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lin Z, McDermott A, Shao L, Kannan A, Morgan M, Stack Jr BC, et al. Chronic mTOR activation promotes cell survival in Merkel cell carcinoma. Cancer Lett. 2014;344(2):272–81. doi:10.1016/j.canlet.2013.11.005.

    Article  CAS  PubMed  Google Scholar 

  20. Kannan A, Lin Z, Shao Q, Zhao S, Fang B, Moreno MA, et al. Dual mTOR inhibitor MLN0128 suppresses Merkel cell carcinoma (MCC) xenograft tumor growth. Oncotarget. 2015;7:6576–92. doi:10.18632/oncotarget.5878.

    PubMed Central  Google Scholar 

  21. Ben-Hur V, Denichenko P, Siegfried Z, Maimon A, Krainer A, Davidson B, et al. S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1. Cell Rep. 2013;3(1):103–15. doi:10.1016/j.celrep.2012.11.020.

    Article  CAS  PubMed  Google Scholar 

  22. Ola MS, Nawaz M, Ahsan H. Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem. 2011;351(1–2):41–58. doi:10.1007/s11010-010-0709-x.

    Article  CAS  PubMed  Google Scholar 

  23. Silvera D, Formenti SC, Schneider RJ. Translational control in cancer. Nat Rev Cancer. 2010;10(4):254–66. doi:10.1038/nrc2824.

    Article  CAS  PubMed  Google Scholar 

  24. Holz MK, Blenis J. Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J Biol Chem. 2005;280(28):26089–93. doi:10.1074/jbc.M504045200.

    Article  CAS  PubMed  Google Scholar 

  25. Dibble CC, Asara JM, Manning BD. Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol. 2009;29(21):5657–70. doi:10.1128/MCB.00735-09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 2004;4(5):335–48. doi:10.1038/nrc1362.

    Article  CAS  PubMed  Google Scholar 

  27. Brett D, Pospisil H, Valcarcel J, Reich J, Bork P. Alternative splicing and genome complexity. Nat Genet. 2002;30(1):29–30. doi:10.1038/ng803.

    Article  CAS  PubMed  Google Scholar 

  28. Lin JC, Lin CY, Tarn WY, Li FY. Elevated SRPK1 lessens apoptosis in breast cancer cells through RBM4-regulated splicing events. RNA. 2014;20(10):1621–31. doi:10.1261/rna.045583.114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Choi HN, Jin HO, Kim JH, Hong SE, Kim HA, Kim EK, et al. Inhibition of S6K1 enhances glucose deprivation-induced cell death via downregulation of anti-apoptotic proteins in MCF-7 breast cancer cells. Biochem Biophys Res Commun. 2013;432(1):123–8. doi:10.1016/j.bbrc.2013.01.074.

    Article  CAS  PubMed  Google Scholar 

  30. Hong SE, Kim EK, Jin HO, Kim HA, Lee JK, Koh JS, et al. S6K1 inhibition enhances tamoxifen-induced cell death in MCF-7 cells through translational inhibition of Mcl-1 and survivin. Cell Biol Toxicol. 2013;29(4):273–82. doi:10.1007/s10565-013-9253-2.

    Article  CAS  PubMed  Google Scholar 

  31. 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(2):163–75.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (No. 81402576, No. 81402408) and the Fundamental Research Funds for the Central Universities (No. 2014QN052, No. 2014QN041).

Author information

Authors and Affiliations

  1. Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan, 430022, China

    Hong Mei

  2. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan, 430022, China

    Ye Wang, Jiquan Fan & Zhenyu Lin

Authors
  1. Hong Mei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ye Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiquan Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhenyu Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhenyu Lin.

Ethics declarations

All animal experiments were performed under a protocol approved by the university’s Institutional Animal Care and Use Committee.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mei, H., Wang, Y., Fan, J. et al. Alternative splicing of S6K1 promotes non-small cell lung cancer survival. Tumor Biol. 37, 13369–13376 (2016). https://doi.org/10.1007/s13277-016-5253-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5253-1

Keywords

Search

Navigation