CXCL12/CXCR4 signaling counteracts docetaxel-induced microtubule stabilization via p21-activated kinase 4-dependent activation of LIM domain kinase 1

Oncotarget. 2014 Nov 30;5(22):11490-500. doi: 10.18632/oncotarget.2571.


Emerging data highlight the significance of chemokine (C-X-C motif) ligand 12/chemokine (C-X-C motif) receptor 4 (CXCL12/CXCR4) signaling axis in the chemoresistance of several malignancies, including prostate cancer (PCa); however, underlying mechanisms remain largely elusive. Here, we demonstrate that CXCL12 treatment rescues the PCa cells from docetaxel (DTX)-induced toxicity by overriding its effect on cell cycle (G2/M phase arrest). We further demonstrate that the chemoprotective effect of CXCL12 is abolished upon pharmacological inhibition or RNA interference-mediated silencing of CXCR4. Moreover, microtubule stabilization caused by DTX is suppressed in CXCL12-stimulated PCa cells as revealed by immunofluorescence and immunoblot analyses. The effect of CXCL12 on microtubule stabilization is abrogated when PCa cells are pre-treated with a CXCR4 antagonist. In additional studies, we show that the chemoprotective action of CXCL12/CXCR4 signaling is mediated by p21-activated kinase 4 (PAK4)-dependent activation of Lim domain kinase 1 (LIMK1), and inhibition of either PAK4 or LIMK1 leads to re-sensitization of PCa cells to DTX-induced tubulin polymerization and cellular toxicity even in the presence of CXCL12. Altogether, our findings uncover a novel mechanism underlying CXCL12/CXCR4 signaling-induced PCa chemoresistance and suggest that targeting of this signaling axis or its downstream effector pathway could lead to therapeutic enhancement of DTX.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anticarcinogenic Agents / chemistry
  • Cell Cycle
  • Cell Division
  • Cell Line, Tumor
  • Chemokine CXCL12 / metabolism*
  • Docetaxel
  • Drug Resistance, Neoplasm
  • G2 Phase
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lim Kinases / metabolism*
  • Male
  • Microscopy, Fluorescence
  • Microtubules / metabolism*
  • Phosphorylation
  • Prostatic Neoplasms / metabolism*
  • RNA Interference
  • Receptors, CXCR4 / metabolism*
  • Signal Transduction
  • Taxoids / chemistry*
  • p21-Activated Kinases / metabolism*


  • Anticarcinogenic Agents
  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Receptors, CXCR4
  • Taxoids
  • Docetaxel
  • PAK4 protein, human
  • LIMK1 protein, human
  • Lim Kinases
  • p21-Activated Kinases