Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy

Abstract

Evading apoptosis is considered to be a hallmark of cancer, because mutations in apoptotic regulators invariably accompany tumorigenesis1. Many chemotherapeutic agents induce apoptosis, and so disruption of apoptosis during tumour evolution can promote drug resistance2. For example, Akt is an apoptotic regulator that is activated in many cancers and may promote drug resistance in vitro3. Nevertheless, how Akt disables apoptosis and its contribution to clinical drug resistance are unclear. Using a murine lymphoma model, we show that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E, a translational regulator that acts downstream of Akt and mTOR, recapitulates Akt's action in tumorigenesis and drug resistance, but is unable to confer sensitivity to rapamycin and chemotherapy. These results establish Akt signalling through mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in vivo, and reveal how targeting apoptotic programmes can restore drug sensitivity in a genotype-dependent manner.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2: Akt accelerates lymphomagenesis and promotes drug resistance in vivo.
Figure 3: Inhibition of mTOR sensitizes Akt tumours to cytotoxic chemotherapy.
Figure 4: Rapamycin reverses Akt-mediated chemoresistance in vivo.
Figure 5: eIF4E promotes oncogenesis and drug resistance in vivo.

References

  1. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000)

    CAS  Google Scholar 

  2. Johnstone, R. W., Ruefli, A. A. & Lowe, S. W. Apoptosis: a link between cancer genetics and chemotherapy. Cell 108, 153–164 (2002)

    CAS  Article  Google Scholar 

  3. Mayo, L. D., Dixon, J. E., Durden, D. L., Tonks, N. K. & Donner, D. B. PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J. Biol. Chem. 277, 5484–5489 (2002)

    CAS  Article  Google Scholar 

  4. Datta, S. R., Brunet, A. & Greenberg, M. E. Cellular survival: a play in three Akts. Genes Dev. 13, 2905–2927 (1999)

    CAS  Article  Google Scholar 

  5. Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nature Rev. Cancer 2, 489–501 (2002)

    CAS  Article  Google Scholar 

  6. Steck, P. A. et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nature Genet. 15, 356–362 (1997)

    CAS  Article  Google Scholar 

  7. Sakai, A., Thieblemont, C., Wellmann, A., Jaffe, E. S. & Raffeld, M. PTEN gene alterations in lymphoid neoplasms. Blood 92, 3410–3415 (1998)

    CAS  PubMed  Google Scholar 

  8. Min, Y. H. et al. Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia 17, 995–997 (2003)

    CAS  Article  Google Scholar 

  9. Andjelkovic, M. et al. Role of translocation in the activation and function of protein kinase B. J. Biol. Chem. 272, 31515–31524 (1997)

    CAS  Article  Google Scholar 

  10. Adams, J. M. et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533–538 (1985)

    ADS  CAS  Article  Google Scholar 

  11. Schmitt, C. A. et al. Dissecting p53 tumor suppressor functions in vivo. Cancer Cell 1, 289–298 (2002)

    CAS  Article  Google Scholar 

  12. Schmitt, C. A., Rosenthal, C. T. & Lowe, S. W. Genetic analysis of chemoresistance in primary murine lymphomas. Nature Med. 6, 1029–1035 (2000)

    CAS  Article  Google Scholar 

  13. Schmitt, C. A. et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335–346 (2002)

    CAS  Article  Google Scholar 

  14. Huang, S. & Houghton, P. J. Targeting mTOR signalling for cancer therapy. Curr. Opin. Pharmacol. 3, 371–377 (2003)

    CAS  Article  Google Scholar 

  15. Plas, D. R., Talapatra, S., Edinger, A. L., Rathmell, J. C. & Thompson, C. B. Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology. J. Biol. Chem. 276, 12041–12048 (2001)

    CAS  Article  Google Scholar 

  16. Edinger, A. L. & Thompson, C. B. Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol. Biol. Cell 13, 2276–2288 (2002)

    CAS  Article  Google Scholar 

  17. Neshat, M. S. et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA 98, 10314–10319 (2001)

    ADS  CAS  Article  Google Scholar 

  18. Grunwald, V. et al. Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. Cancer Res. 62, 6141–6145 (2002)

    CAS  PubMed  Google Scholar 

  19. Podsypanina, K. et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice. Proc. Natl Acad. Sci. USA 98, 10320–10325 (2001)

    ADS  CAS  Article  Google Scholar 

  20. Hosoi, H. et al. Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells. Cancer Res. 59, 886–894 (1999)

    CAS  PubMed  Google Scholar 

  21. Schmelzle, T. & Hall, M. N. TOR, a central controller of cell growth. Cell 103, 253–262 (2000)

    CAS  Article  Google Scholar 

  22. Lazaris-Karatzas, A., Montine, K. S. & Sonenberg, N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′ cap. Nature 345, 544–547 (1990)

    ADS  CAS  Article  Google Scholar 

  23. Polunovsky, V. A. et al. Translational control of the antiapoptotic function of Ras. J. Biol. Chem. 275, 24776–24780 (2000)

    CAS  Article  Google Scholar 

  24. Hershey, J. W. B. & Miyamoto, S. in Translational Control of Gene Expression (eds Sonenberg, N., Hershey, J. W. B. & Mathews, M. B.) 637–654 (Cold Spring Harbor, New York, 2000)

    Google Scholar 

  25. Grolleau, A. et al. Global and specific translational control by rapamycin in T cells uncovered by microarrays and proteomics. J. Biol. Chem. 277, 22175–22184 (2002)

    CAS  Article  Google Scholar 

  26. Rajasekhar, V. K. et al. Oncogenic Ras and Akt signalling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol. Cell 12, 889–901 (2003)

    CAS  Article  Google Scholar 

  27. Schmitt, C. A., McCurrach, M. E., de Stanchina, E., Wallace-Brodeur, R. R. & Lowe, S. W. INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. Genes Dev. 13, 2670–2677 (1999)

    CAS  Article  Google Scholar 

  28. Yang, M. et al. Whole-body optical imaging of green fluorescent protein-expressing tumors and metastases. Proc. Natl Acad. Sci. USA 97, 1206–1211 (2000)

    ADS  CAS  Article  Google Scholar 

  29. Di Cristofano, A., De Acetis, M., Koff, A., Cordon-Cardo, C. & Pandolfi, P. P. Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nature Genet. 27, 222–224 (2001)

    CAS  Article  Google Scholar 

  30. de Stanchina, E. et al. E1A signalling to p53 involves the p19(ARF) tumor suppressor. Genes Dev. 12, 2434–2442 (1998)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank M. Myers and N. Sonenberg for reagents; C. Rosenthal, M. S. Jiao, P. Chan, M. L. Maunakea and F. Baehner for technical assistance; and L. Bianco for guidance on animal studies. We also thank C. Thompson and members of the Lowe laboratory for discussions, and M. McCurrach, M. Hemann, E. Cepero and D. Burgess for editorial advice. This work was supported by a gift from the Ann L. and Herbert J. Siegel Philanthropic Fund and the Laurie Strauss Leukaemia Foundation, an AACR/Amgen Fellowship in Translational Research (H.-G.W.), a Tularik Post-doctoral Fellowship (E.d.S), a NSERC graduate scholarship (A.M.), an NCI postdoctoral training grant (J.S.F), grants from Canadian Institutes of Health Research and National Cancer Institute of Canada (J.P.), the Mouse Models of Human Cancer Consortium and a Burroughs Wellcome Fund Career Award (S.K.), a SCOR grant from the Leukaemia and Lymphoma Society (S.K and S.W.L.), and a program project grant from the National Cancer Institute (S.W.L and C.C.-C.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Scott W. Lowe.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure 1

Representative data from flow cytometric immunophenotyping of control (myc), Bcl-2 (myc/bcl-2), Akt (myc/akt) and eIF4E (myc/eIF4E) tumours. (PDF 283 kb)

Supplementary Figure 2

Allele-specific PCR to detect the wild-type (p53 WT) and mutant allele (p53 Neo) in tumours derived from Eµ-myc/p53+/- HSCs. (PDF 51 kb)

Supplementary Figure 3

Kaplan-Meier plots detailing the survival time following treatment with CTX (a) and DXR (b). (PDF 7 kb)

Supplementary Figure 4

Overall survival of mice treated with rapamycin alone or in combination with conventional chemotherapy. (PDF 11 kb)

Supplementary Figure 5

Kaplan-Meier analysis of tumour free survival in Akt tumour bearing mice (a) following treatment with CTX (n = 16, red), RAP (n = 12, blue), or CTX+RAP (C+R, n = 8) and in Bcl-2 tumour bearing mice (b) treated with CTX (n = 6, red), RAP (n = 6, blue) and CTX+RAP (C+R, n=4, green). (PDF 8 kb)

Supplementary Figure 6

Rapamycin reverses chemoresistance in matched Akt-expressing lymphomas. (PDF 4 kb)

Supplementary Figure 7

Quantification of eIF4E expression in lysates derived from Bcl-2 (n=3), Akt (n=5) and eIF4E (n=5) tumours. (PDF 48 kb)

Supplementary Table 1

Immunophenotype of Emmyc tumours expressing Akt, Bcl-2 or eIF4E. PDF, 168kB (PDF 164 kb)

Supplementary Figure Legends (RTF 8 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wendel, HG., Stanchina, E., Fridman, J. et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428, 332–337 (2004). https://doi.org/10.1038/nature02369

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02369

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing