PI3K/Akt signaling: TORmenting prostate cancer

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Inhibition of mammalian target of rapamycin (mTOR) reverses Akt-dependent prostate intraepithelial neoplasia (PIN) in mice through the regulation of both apoptotic and HIF-1 alpha -dependent pathways.

PTEN is a tumor suppressor gene that is frequently deleted or mutated in prostate, endometrial and breast cancer. This lipid phosphatase regulates cell survival, growth and migration by suppressing phosphoinositol 3 kinase (PI3K) signaling, thereby down-regulating downstream mediators, including the oncogenic serine-threonine kinase AKT, which in turn regulates the mTOR (mammalian target of rapamycin) growth pathway. Clinical trials are currently underway to evaluate mTOR inhibition as a viable cancer treatment for PTEN-null cancers. Majumder et al. now show that the anti-tumor response to mTOR inhibition occurs through independent apoptotic and Hif-1 alpha regulatory pathways.

The authors previously found that transgenic mice expressing activated AKT1 in the epithelial cells of the ventral prostate results in a phenotype similar to prostatic intraepithelial neoplasia (PIN). These AKT1-Tg mice showed no signs of PIN after two weeks of treatment with the rapamycin derivative RAD001. RAD001 selectively inhibits mTOR activity downstream of AKT, without altering other elements of Akt signaling; thus, the AKT-dependent PIN phenotype requires mTOR activity.

While investigating the time course of the response to RAD001, the authors noted a lack of proliferating cells, as well as rapid phenotypic reversion and a vacuolated cell appearance. This suggested that the loss of intraluminal cells after RAD001 exposure may be due to apoptosis and that the intraluminal epithelial cells in PIN depend on an mTOR-dependent, antiapoptotic signaling pathway for their survival. Indeed, when AKT1-Tg mice were crossed with transgenic mice expressing BCL2 in the ventral prostate, the progeny exhibited only partial regression of the phenotype when treated with RAD001. This reveals that BCL2 expression blocks the induction of apoptosis by mTOR inhibition and leads to a partial resistance to RAD001. Thus, apoptosis in response to mTOR inhibition requires the mitochondrial apoptotic pathway.

Gene expression profiling was carried out to determine if another pathway is involved in RAD001 inhibition of PIN. This sceen identified a set of hypoxia-inducible factor 1 (HIF-1) target genes that were induced in the transgenic mice, and repressed by RAD001. Indeed, HIF-1 alpha activity was found to be upregulated in both AKT and AKT/BCL2-expressing tumors, and downregulated after RAD001 administration. These changes preceeded any phenotypic changes and are likely to be direct, thus pointing to a functional role for HIF-1 alpha in this pathway.

Together, these results define two mechanisms likely to be instrumental in the anti-oncogenic response of mTOR inhibition. Prostate cancer patients with overexpression of BCL2 in tumors, or TOR-independent activation of HIF-1 alpha , may be less responsive to mTOR inhibition treatment. This may allow tailoring of prostatic cancer treatments to patients.

Brenda Riley, Assistant Editor
Signaling Gateway

References

Majumder, Pradip K, Febbo, Phillip G, Bikoff, Rachel, Berger, Raanan, Xue, Qi, McMahon, Louis M, Manola, Judith, Brugarolas, James, McDonnell, Timothy J, 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. Nature Medicine, 10, 594–601 (2004); 10.1038/nm1052 | Article | PubMed |
Mellinghoff, Ingo K, & Sawyers, Charles L TORward AKTually useful mouse models. Nature Medicine, 10, 579–580 (2004); 10.1038/nm0604-579 | Article | PubMed |