Etoposide induces growth arrest and disrupts androgen receptor signaling in prostate cancer cells.
Androgen and androgen receptor (AR)-mediated signaling are crucial for the development of prostate cancer. The present study indicates that the topoisomerase II inhibitor etoposide strikingly inhibits androgen/AR-mediated cell growth and androgen-stimulated DNA synthesis in prostate cancer cells. Etoposide significantly repressed the AR mRNA and protein expression in a dose-dependent manner. Etoposide-mediated down-regulation of AR was associated with blocking androgen-induced AR translocation from cytoplasm into nucleus of cells. Additionally, etoposide disrupted the association of AR and heat shock protein 90 and impeded binding of the synthetic androgen [3H]R1881 to AR in LNCaP cells. Etoposide simultaneously reduced the intracellular and secreted PSA levels, a marker for the progression of prostate cancer. These findings collectively reveal that etoposide not only serves as a traditional genotoxic agent but directly targets AR as an AR disrupting therapeutic strategy in prostate cancer.
Liu
Shicheng
S
Department of Research and Development, Nipro Patch Co., Ltd., Kasukabe, Saitama, Japan. liu@nipro-patch.co.jp
Yamauchi
Hitoshi
H
D021581:Active Transport, Cell Nucleus; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions
D000972:Antineoplastic Agents, Phytogenic; D011944:Receptors, Androgen; D005047:Etoposide