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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.

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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.

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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.).

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Correspondence to Scott W. Lowe.

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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)

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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

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