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

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

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

“…mTOR inhibitors induce apoptosis in some types of tumor cells (Hosoi et al, 1999;Nepomuceno et al, 2003;Majumder et al, 2004;Avellino et al, 2005), whereas they trigger autophagy in other settings (Noda and Ohsumi, 1998;Gutierrez et al, 2004;Kanazawa et al, 2004;Ravikumar et al, 2004) as well as in malignant glioma cells as shown in this study and our previous investigation (Takeuchi et al, 2005). Autophagy is a process by which cells degrade and recycle proteins and intracellular components in response to stress or starvation (Klionsky and Emr, 2000;Levine and Klionsky, 2004;Shintani and Klionsky, 2004).…”

A gene transcription signature of the Akt/mTOR pathway in clinical breast tumors

“…In the study by Majumder et al (2004), a probasin promoter-myr-HA-AKT1 transgene was used to direct production of activated Akt1 spatially restricted to the luminal epithelial cells of the mouse ventral prostrate (AKT1-Tg). The AKT1-Tg mice developed a highly penetrant prostatic intraepithelial neoplasia (PIN) phenotype.…”

“…This PIN phenotype was completely dependent on mTOR activation, as treatment with mTOR inhibitor RAD001 induced apoptosis and reversed the PIN phenotype within 2 weeks. To identify genes altered by Akt expression and by subsequent mTOR inhibition, Majumder et al (2004) prepared total RNA after 12 or 48 h of RAD001 or placebo treatment in wild-type and AKT1-Tg mouse prostate, and message abundance was determined for over 20 000 genes using microarrays. From this expression profile data set, it was determined that gene targets of mTOR inhibition were enriched for Hif-1 targets and glycolysis genes (Majumder et al, 2004).…”

“…To date, no mRNA signature has been defined for the Akt pathway in human breast cancer. A recent study by Majumder et al (2004) carried out global gene expression profiling of a transgenic mouse model of Akt activation, although the observed expression patterns were not examined in clinical tumor specimens. This study describes a meta-analysis combining Majumder's data with five independent expression profile data sets of human breast tumors (van de Vijver et al, 2002;Sorlie et al, 2003;Ma et al, 2004;Miller et al, 2005;Wang et al, 2005), with the goal of determining whether a gene signature of Akt in human breast cancer can be defined and in which tumor subtypes the pathway appears to be deregulated.…”

Down‐regulation of PKM2 enhances anticancer efficiency of THP on bladder cancer

“…Pyruvate kinase (PK) regulates the final rate‐limiting step of glycolysis and catalyses the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate 14. This transfer yields one molecule each of pyruvate and adenosine triphosphate 15, 16. PKM1, PKM2, PKL and PKR are PK isoforms expressed in different types of mammalian cells and tissues.…”