Androgen receptor as a licensing factor for DNA replication in androgen-sensitive prostate cancer cells.
Androgen receptor (AR) protein expression and function are critical for survival and proliferation of androgen-sensitive (AS) prostate cancer cells. Besides its ability to function as a transcription factor, experimental observations suggest that AR becomes a licensing factor for DNA replication in AS prostate cancer cells and thus must be degraded during each cell cycle in these cells to allow reinitiation of DNA replication in the next cell cycle. This possibility was tested by using the AS human prostate cancer cell lines, LNCaP, CWR22Rv1, and LAPC-4. These studies demonstrated that AR levels fluctuate both within and between various phases of the cell cycle in each of these AS lines. Consistent with its licensing ability, AR is degraded during mitosis via a proteasome-dependent pathway in these AS prostate cancer cells. In contrast, proteasome-dependent degradation of AR during mitosis is not observed in AR-expressing but androgen-insensitive human prostate stromal cells, in which AR does not function as a licensing factor for DNA replication. To evaluate mitotic degradation of AR in vivo, the same series of human AS prostate cancers growing as xenografts in nude mice and malignant tissues obtained directly from prostate cancer patients were evaluated by dual Ki-67 and AR immunohistochemistry for AR expression in mitosis. These results document that AR is also down-regulated during mitosis in vivo. Thus, AS prostate cancer cells do not express AR protein during mitosis, either in vitro or in vivo, consistent with AR functioning as a licensing factor for DNA replication in AS prostate cancer cells.
Litvinov
Ivan V
IV
Chemical Therapeutics Program, Division of Immunology and Hematopoiesis, The Sidney Kimmel Comprehensive Cancer Center, Department of Pathology, and the Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Vander Griend
Donald J
DJ
Antony
Lizamma
L
Dalrymple
Susan
S
De Marzo
Angelo M
AM
Drake
Charles G
CG
Isaacs
John T
JT
D059002:Androgen Receptor Antagonists; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D004261:DNA Replication / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000502:physiology*; D014407:Tumor Cells, Cultured
D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen