Mitogenic action of the androgen receptor sensitizes prostate cancer cells to taxane-based cytotoxic insult.
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 taxane-induced cell death is significantly enhanced by androgen stimulation in AR-positive, androgen-dependent prostate cancer cells. Similar results were observed on androgen-independent 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.
Hess-Wilson
Janet K
JK
Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Daly
Hannah K
HK
Zagorski
William A
WA
Montville
Christopher P
CP
Knudsen
Karen E
KE
D000728:Androgens / Q000502:physiology; D001952:Bridged-Ring Compounds / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers; D006801:Humans; D008297:Male; D015162:Micronucleus Tests; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics; D011944:Receptors, Androgen / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids / Q000627:therapeutic use*
D000728:Androgens; D001952:Bridged-Ring Compounds; D017931:DNA Primers; D012334:RNA, Neoplasm; D011944:Receptors, Androgen; D043823:Taxoids; C080625:taxane; D017430:Prostate-Specific Antigen