title: The significance of Her2 on androgen receptor protein stability in the transition of androgen requirement in prostate cancer cells.
abstract: Androgen ablation therapy is the most common strategy for suppressing prostate cancer progression; however, tumor cells eventually escape androgen dependence and progress to an androgen-independent phase. The androgen receptor (AR) plays a pivotal role in this transition. To address this transition mystery in prostate cancer, we established an androgen-independent prostate cancer cell line (LNCaPdcc), by long-term screening of LNCaP cells in androgen-deprived conditions, to investigate changes of molecular mechanisms before and after androgen withdrawal. We found that LNCaPdcc cells displayed a neuroendocrine morphology, less aggressive growth, and lower expression levels of cell cycle-related factors, although the cell cycle distribution was similar to parental LNCaP cells. Notably, higher protein expression of AR, phospho-Ser(81)-AR, and PSA in LNCaPdcc cells were observed. The nuclear distribution and protein stability of AR increased in LNCaPdcc cells. In addition, cell proliferation results exhibited the biphasic nature of the androgen (R1881) effect in two cell lines. On the other hand, LNCaPdcc cells expressed higher levels of Her2, phospho-Tyr(1221/1222)-Her2, ErbB3, and ErbB4 proteins than parental LNCaP cells. These two cell lines exhibited distinct responses to Her2 activation (by heregulin treatment) on Her2 phosphorylation and Her2 inhibition (by AG825 or Herceptin treatments) on proliferation. In addition, the Her2 inhibitor more effectively caused AR degradation and diminished AR Ser(81) phosphorylation in LNCaPdcc cells. Taken together, our data demonstrate that Her2 plays an important role in the support of AR protein stability in the transition of androgen requirement in prostate cancer cells. We hope these findings will provide novel insight into the treatment of hormone-refractory prostate cancer.
authors.affiliation: Dept. of Life Sciences, National Chung Hsing University, 250 Kuo Kuang Rd., Taichung 40227, Taiwan.
authors.forename: Fu-Ning
authors.initials: FN
authors.lastname: Hsu
authors.forename: Min-Shiou
authors.initials: MS
authors.lastname: Yang
authors.forename: Eugene
authors.initials: E
authors.lastname: Lin
authors.forename: Chun-Fu
authors.initials: CF
authors.lastname: Tseng
authors.forename: Ho
authors.initials: H
authors.lastname: Lin
mesh_terms: D000728:Androgens / Q000494:pharmacology / Q000502:physiology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism*; D000068878:Trastuzumab; D014343:Trypan Blue; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000728:Androgens; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D015741:Metribolone; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; D000068878:Trastuzumab; D014343:Trypan Blue; D020032:Tyrphostins; C098214:tyrphostin AG825; C508053:ERBB2 protein, human