Stabilizing androgen receptor in mitosis inhibits prostate cancer proliferation.
The androgen receptor (AR) is a steroid transcription factor, the activity of which is the primary focus of androgen ablation therapies for advanced prostate cancer. In prostate cancers, the AR acquires gain-of-function changes allowing it to drive prostate cancer cell survival and proliferation in a cell-autonomous manner. As part of this malignancy-associated gain-of-function, AR acquires a role in licensing for DNA replication in prostate cancer cells. In its role as a licensing factor, AR must be degraded during mitosis in order to allow relicensing in the subsequent cell cycle. This conclusion is supported by the demonstration that acute enhanced expression of AR in prostate cancer cells results in its incomplete degradation in mitosis. This lack of mitotic AR degradation inhibits subsequent cell proliferation due to the inability to relicense all origins of replication needed for the next round of cell division. These data provide a unifying paradigm to clarify a number of unresolved observations in prostate cancer research. In addition, they provide a rationale for a new therapeutic approach for prostate cancer based upon stabilization of AR.
Vander Griend
Donald J
DJ
Chemical Therapeutics Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Litvinov
Ivan V
IV
Isaacs
John T
JT
D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D059002:Androgen Receptor Antagonists; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen