Reference SummaryMajumder PK, Nat Med 2004 Jun;10(6):594-601

Title

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

Authors

Majumder PK; Febbo PG; Bikoff R; Berger R; Xue Q; McMahon LM; Manola J; Brugarolas J; McDonnell TJ; Golub TR; Loda M; Lane HA; Sellers WR

Journal

Nat Med

Volume

10

Issue

6

Year

2004

Pages

594-601

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-1alpha 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-1alpha, and that clinical resistance to mTOR inhibitors may emerge through BCL2 expression and/or upregulation of HIF-1alpha activity.

Links

15156201 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
FVB Prostate gland - Ventral lobe neoplasia Prostate gland - Ventral lobe

0

FVB Prostate gland - Ventral lobe prostatic intraepithelial neoplasia (PIN)
  • 40-O-(2-hydroxyethyl)-rapamycin
Prostate gland - Ventral lobe

0

FVB-Tg(Pbsn-AKT1)9Wrs Prostate gland - Ventral lobe prostatic intraepithelial neoplasia (PIN) Prostate gland - Ventral lobe

very high

FVB-Tg(Pbsn-AKT1)9Wrs Prostate gland - Ventral lobe prostatic intraepithelial neoplasia (PIN)
  • 40-O-(2-hydroxyethyl)-rapamycin
Prostate gland - Ventral lobe

0

B6;FVB-Tg(BCL2)#Tjd Tg(Pbsn-AKT1)9Wrs Prostate gland - Ventral lobe prostatic intraepithelial neoplasia (PIN)
  • 40-O-(2-hydroxyethyl)-rapamycin
Prostate gland - Ventral lobe

observed