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 |
J:90631 – MGI References 15156201 – National Library of Medicine/PubMed |
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) |
|
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) |
|
Prostate gland - Ventral lobe |
0 |
|
B6;FVB-Tg(BCL2)#Tjd Tg(Pbsn-AKT1)9Wrs | Prostate gland - Ventral lobe prostatic intraepithelial neoplasia (PIN) |
|
Prostate gland - Ventral lobe |
observed |