title: Plk1-dependent microtubule dynamics promotes androgen receptor signaling in prostate cancer.
abstract: BACKGROUND
  The androgen receptor (AR) signaling continues to be essential in castrate-resistant prostate cancer (CRPC). Taxel-based chemotherapy is the current standard treatment for CRPC patients. Unfortunately, almost all patients eventually develop resistance toward this chemotherapy. Significantly, it was recently found that the anti-tumor effect of paclitaxel in CRPC is due to its inhibition of AR activity via its inhibition of microtubule dynamics. Polo-like kinase 1 (Plk1), a critical regulator in many cell cycle events, is elevated in prostate cancer (PCa) and linked to tumor grades. Of note, we have previously shown that Plk1 phosphorylates CLIP-170 and p150(Glued) , two important regulators of microtubule dynamics.
  
  
  METHODS
  We compared paclitaxel-mediated phenotypes (inhibition of the AR signaling, decrease of microtubule dynamics and cell death) of PCa cells expressing different forms of CLIP-170 and p150(Glued) with different Plk1 phosphorylation states.
  
  
  RESULTS
  We show that Plk1 phosphorylation of CLIP-170 and p150(Glued) affects cellular responses to paclitaxel. Expression of Plk1-unphosphorylatable mutants of CLIP-170 and p150(Glued) results in increased paclitaxel-induced apoptosis, increased protein degradation of the AR, and decreased nuclear accumulation of the AR in response to androgen in prostate cancer cells. Finally, we show that cells expressing unphosphorylatable mutants of CLIP-170 have defective microtubule dynamics, thus providing a new mechanism to understand how Plk1-associated kinase activity promotes constitutive activation of AR signaling in CRPC.
  
  
  CONCLUSIONS
  Our data suggest that a combination of inhibition of Plk1 and paclitaxel might be a novel avenue for treatment of CRPC.
authors: Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA.
authors: Xianzeng
authors: X
authors: Hou
authors: Zhiguo
authors: Z
authors: Li
authors: Weize
authors: W
authors: Huang
authors: Jiejie
authors: J
authors: Li
authors: Christopher
authors: C
authors: Staiger
authors: Shihuan
authors: S
authors: Kuang
authors: Tim
authors: T
authors: Ratliff
authors: Xiaoqi
authors: X
authors: Liu
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D017239:Paclitaxel; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D000097869:Polo-Like Kinase 1; C410798:AR protein, human
keywords: Plk1; androgen receptor; microtubule dynamics; paclitaxel; prostate cancer
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