The complex role of AR signaling after cytotoxic insult: implications for cell-cycle-based chemotherapeutics.
Prostatic adenocarcinomas are dependent on androgen receptor (AR) signaling for growth and progression, in part through the ability of AR to induce G1-S phase cell cycle transition. Hormonal therapies that inhibit AR activity are the first line of intervention for disseminated disease, and are initially quite effective; however, recurrent, incurable tumors ultimately arise with restored AR function. Given the importance of AR in governing the potentiation of this tumor type, there has been a dedicated interest in dissecting the mechanisms by which AR promotes prostate cancer proliferation and survival. Recent studies have challenged the utility of manipulating AR activity to enhance cell death in combination with genotoxic insult. Herein, the role of AR in controlling cell cycle progression and paradoxical roles of AR in survival signals are considered, as are the potential implications of these findings for chemotherapeutic response. Although there is much to be resolved, the present data suggest that knowledge of AR action in promoting cellular proliferation can be utilized for the design of coordinate strategies that maximize cell death in response to cytotoxic chemotherapeutics.
Comstock
Clay E S
CE
Department of Cell and Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Knudsen
Karen E
KE
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008297:Male; D008870:Microtubules / Q000187:drug effects; D050258:Mitosis Modulators / Q000494:pharmacology / Q000627:therapeutic use; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000502:physiology*; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D050258:Mitosis Modulators; D009363:Neoplasm Proteins; D011944:Receptors, Androgen