title: CXCL12/CXCR4 signaling counteracts docetaxel-induced microtubule stabilization via p21-activated kinase 4-dependent activation of LIM domain kinase 1.
abstract: 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.
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Bhardwaj
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Srivastava
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors.forename: Seema
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Arora
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Tyagi
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Andrews
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: McClellan
authors.affiliation: Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Carter
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA. Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
authors.forename: Ajay P
authors.initials: AP
authors.lastname: Singh
mesh_terms: D016588:Anticarcinogenic Agents / Q000737:chemistry; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D016195:G2 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D054461:Lim Kinases / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D034622:RNA Interference; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D043823:Taxoids / Q000737:chemistry*; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D043823:Taxoids; D000077143:Docetaxel; C116367:PAK4 protein, human; C515892:LIMK1 protein, human; D054461:Lim Kinases; D054462:p21-Activated Kinases