Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival

Abstract

The mTOR (mammalian target of rapamycin) inhibitor rapamycin caused growth arrest in both androgendependent and androgen-independent prostate cancer cells; however, long-term treatment induced resistance to the drug. The aim of this study was to investigate methods that can overcome this resistance. Here, we show that rapamycin treatment stimulated androgen receptor (AR) transcriptional activity, whereas suppression of AR activity with the antiandrogen bicalutamide sensitized androgen-dependent, as well as AR-sensitive androgenindependent prostate cancer cells, to growth inhibition by rapamycin. Further, the combination of rapamycin and bicalutamide, but not the individual drugs, induced significant levels of apoptosis in prostate cancer cells. The net effect of rapamycin is determined by its individual effects on the mTOR complexes mTORC1 (mTOR/ raptor/GbL) and mTORC2 (mTOR/rictor/sin1/GbL). Inhibition of both mTORC1 and mTORC2 by rapamycin-induced apoptosis, whereas rapamycin-stimulation of AR transcriptional activity resulted from the inhibition of mTORC1, but not mTORC2. The effect of rapamycin on AR transcriptional activity was mediated by the phosphorylation of the serine/threonine kinase Akt, which also partially mediated apoptosis induced by rapamycin and bicalutamide. These results indicate the presence of two parallel cell-survival pathways in prostate cancer cells: a strong Akt-independent, but rapamycin-sensitive pathway downstream of mTORC1, and an AR-dependent pathway downstream of mTORC2 and Akt, that is stimulated by mTORC1 inhibition. Thus, the combination of rapamycin and bicalutamide induce apoptosis in prostate cancer cells by simultaneously inhibiting both pathways and hence would be of therapeutic value in prostate cancer treatment.

Activation of AR Sensitizes Breast Carcinomas to NVP-BEZ235's Therapeutic Effect Mediated by PTEN and KLLN Upregulation

“…S6A). Similar adverse effects have been shown among other mTOR inhibitors, such as RAD001 and rapamycin (1,3). Combining DHT with NVP-BEZ235 effectively prevents this elevation in AKT phosphorylation (Supplementary Fig.…”

“…For example, combining the ER inhibitor tamoxifen and a PI3K inhibitor in breast cancers achieves a better therapeutic effect than either single drug alone (34). Studies have also shown that combination of mTOR inhibitors and AR antagonists could effectively treat advanced prostate cancer (1,35).…”

“…AR activity assay was measured by dual luciferase assay as described previously (1). AR transcriptional activity was measured by Cignal report assay kit (SA Bioscience) as per the manufacturer's instructions.…”

“…The PI3K/AKT/mTOR inhibitors (PI3K/AKT/ mTORi) have shown some promise in clinical trials for patients with cancer. However, long-term inhibition of the PI3K/AKT/mTOR signaling pathway could lead to drug resistance and apparent failure of the therapeutic trials (1)(2)(3). NVP-BEZ235 is a newly developed dual PI3K/mTOR inhibitor, currently being tested in multiple clinical trials for its antiproliferative effects in cancer.…”

WOMEN IN CANCER PROFILE: From physics to cancer biology and everywhere in between

“…Colin also showed a synergistic effect of the combination of the anti-androgen bicalutamide, and the mTOR inhibitor rapamycin in CaP cell lines (Wang et al 2008). The basic premise was that in non-tumor prostate, the mTOR pathway promotes AR transcriptional activity, whereas in castration-resistant tissue, mTOR has the opposite effect.…”