mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways

Pradip K. Majumder, Phillip G. Febbo, Rachel Bikoff, Raanan Berger, Qi Xue, Louis M. McMahon, Judith Manolal, James Brugarolas, Timothy J McDonnell, Todd R. Golub, Massimo Loda, Heidi A. Lane, William R. Sellers

Research output: Contribution to journalArticle

776 Citations (Scopus)

Abstract

Loss of PTEN function leads to activation of phosphoinositide 3-kinase (PI3K) signaling and Akt. Clinical trials are now testing whether mammalian target of rapamycin (mTOR) inhibition is useful in treating PTEN-null cancers. Here, we report that mTOR inhibition induced apoptosis of epithelial cells and the complete reversal of a neoplastic phenotype in the prostate of mice expressing human AKT1 in the ventral prostate. Induction of cell death required the mitochondrial pathway, as prostate-specific coexpression of BCL2 blocked apoptosis. Thus, there is an mTOR-dependent survival signal required downstream of Akt. Bcl2 expression, however, only partially restored intraluminal cell growth in the setting of mTOR inhibition. Expression profiling showed that Hif-1α targets, including genes encoding most glycolytic enzymes, constituted the dominant transcriptional response to AKT activation and mTOR inhibition. These data suggest that the expansion of AKT-driven prostate epithelial cells requires mTOR-dependent survival signaling and activation of HIF-1α, and that clinical resistance to mTOR inhibitors may emerge through BCL2 expression and/or upregulation of HIF-1α activity.

Original languageEnglish (US)
Pages (from-to)594-601
Number of pages8
JournalNature Medicine
Volume10
Issue number6
DOIs
StatePublished - Jun 2004

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Sirolimus
Prostate
Neoplasms
Chemical activation
Epithelial Cells
Apoptosis
Gene encoding
1-Phosphatidylinositol 4-Kinase
Survival
Cell growth
Cell death
Phosphatidylinositols
Cell Death
Phosphotransferases
Up-Regulation
Clinical Trials
Phenotype
Testing
Enzymes
Growth

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Majumder, P. K., Febbo, P. G., Bikoff, R., Berger, R., Xue, Q., McMahon, L. M., ... Sellers, W. R. (2004). mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nature Medicine, 10(6), 594-601. https://doi.org/10.1038/nm1052

mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. / Majumder, Pradip K.; Febbo, Phillip G.; Bikoff, Rachel; Berger, Raanan; Xue, Qi; McMahon, Louis M.; Manolal, Judith; Brugarolas, James; J McDonnell, Timothy; Golub, Todd R.; Loda, Massimo; Lane, Heidi A.; Sellers, William R.

In: Nature Medicine, Vol. 10, No. 6, 06.2004, p. 594-601.

Research output: Contribution to journalArticle

Majumder, PK, Febbo, PG, Bikoff, R, Berger, R, Xue, Q, McMahon, LM, Manolal, J, Brugarolas, J, J McDonnell, T, Golub, TR, Loda, M, Lane, HA & Sellers, WR 2004, 'mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways', Nature Medicine, vol. 10, no. 6, pp. 594-601. https://doi.org/10.1038/nm1052
Majumder, Pradip K. ; Febbo, Phillip G. ; Bikoff, Rachel ; Berger, Raanan ; Xue, Qi ; McMahon, Louis M. ; Manolal, Judith ; Brugarolas, James ; J McDonnell, Timothy ; Golub, Todd R. ; Loda, Massimo ; Lane, Heidi A. ; Sellers, William R. / mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. In: Nature Medicine. 2004 ; Vol. 10, No. 6. pp. 594-601.
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