Mitogenic Action of the Androgen Receptor Sensitizes Prostate Cancer Cells to Taxane-Based Cytotoxic Insult

Abstract

Prostate cancer cells are dependent on androgen for growth and survival; as such, inhibition of androgen receptor (AR) activity is the first line of intervention for disseminated disease. Recently, specific cytotoxic agents have been shown to extend survival times in patients with advanced disease. Given the established ability of androgen to modify cell survival in prostate cancer cells, it is imperative to determine the effect of the hormonal environment on cytotoxic response. Here, we show that the response of prostate cancer cells to taxaneinduced cell death is significantly enhanced by androgen stimulation in AR-positive, androgen-dependent prostate cancer cells. Similar results were observed on androgenindependent AR activation. By contrast, AR-positive yet androgen-independent or AR-negative cells were refractory to androgen influence on taxane function. The ability of androgen to potentiate taxane activity was dependent on its mitogenic capacity and was separable from overall AR activity, as coadministration of AR antagonists, G 1 cyclin-dependent kinase inhibitors, or high-dose (growth inhibitory) androgen nullified the proapoptotic function of androgen. Observed induction of cell death was attributed to caspase-dependent apoptosis and correlated with p53 activation. Combined, these data indicate that the cytotoxic effects of taxanes are substantially influenced by the hormonal environment and/or status of AR activity in prostate cancer cells and provide the foundation for refinement and optimization of cytotoxic intervention in prostate cancer.

Androgen receptor expression is a significant prognostic factor in estrogen receptor positive breast cancers

“…One of the most difficult challenges in treating these patients, however, is the identification of patients with incompletely endocrine-responsive tumor who should receive a chemo-endocrine treatment. In prostate cancer, it has been suggested that knowledge of AR action in promoting cell proliferation can be used to design strategies that maximize cell death in response to cytotoxic therapy [27]. The results of the present study suggest that AR could be an important parameter for designing specific systemic treatments for the patients with ER-positive breast cancer.…”

Retinoblastoma Tumor Suppressor Status Is a Critical Determinant of Therapeutic Response in Prostate Cancer Cells

“…shCon1 LNCaP cells and L4-shCon LAPC-4 cells (7.8 Â 10 5 cells per 10-cm dish) were infected with p16INK4a adenovirus for 12 h as previously described (19). Following wash PBS, cells were cultured for an additional 36 to 48 h and then fixed in 95% ethanol, stained with propidium iodide (0.2 Ag/AL), and subjected to flow cytometry as described previously (20). Histograms represent f10,000 cells.…”

Hypoxia, notch signalling, and prostate cancer

“…Recent studies have reported that response to taxanes, the only chemotherapeutic agent proven to be efficacious in prolonging overall survival in patients with prostate cancer, is maximized under conditions of AR activity. 88 On the other hand, HIF-1α overexpression in hypoxic cells has been shown to reduce the effectiveness of microtubule-disrupting agents in a drug-dose-dependent manner in human ovarian cell lines. 89 Similarly, we have reported sensitivity of hypoxic prostate cancer cells to docetaxel and a novel microtubule disrupting agent pyrrolo-1,5-benzoxazepine 15 (PBOX-15).…”