title: miR-138-Mediated Regulation of KINDLIN-2 Expression Modulates Sensitivity to Chemotherapeutics.
abstract: Prostate cancer is the second leading cause of cancer-related death in men, second only to lung cancer, mainly due to disease reoccurrence as a result to lack of response to androgen deprivation therapies (ADT) after castration. Patients with metastatic castration-resistant prostate cancer (mCRPC) have very limited treatment options, with docetaxel as the first-line standard of care, for which resistance to this chemotherapeutic ultimately develops. Therefore, finding ways to sensitize tumors to chemotherapies and to limit chemoresistance provides a viable strategy to extend the survival of mCRPC patients. This study investigated the role of Kindlin-2 (FERMT2/K2), a member of the Kindlin family of FERM domain proteins and key regulators of the adhesive functions mediated by integrin, in the sensitization of mCRPC to chemotherapeutics. Loss of K2, which is overexpressed in prostate cancer cells derived from mCRPC tumors, compared with those cells derived from androgen-dependent tumors, significantly enhanced apoptosis and cell death of docetaxel-treated PC3 cells. Furthermore, it was determined that K2-mediated sensitization to docetaxel treatment is the result of inhibition of β1-integrin signaling. Finally, miR-138 specifically targeted K2 and inhibited its expression, thereby regulating a miR-138/K2/β1-integrin signaling axis in mCRPC that is critical for the modulation of sensitivity to chemotherapeutics. Thus, these data identify a novel signaling axis where K2 in combination with chemotherapeutics provides a new target for the treatment of mCRPC.
  
  
  CONCLUSIONS
  Targeted inhibition of Kindlin-2 in combination with chemotherapy represents an effective treatment option for mCRPC.
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. sosseyk@ccf.org.
authors.forename: Khalid
authors.initials: K
authors.lastname: Sossey-Alaoui
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Plow
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C477322:FERMT3 protein, human; D019012:Integrin beta1; C546110:MIRN138 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D009363:Neoplasm Proteins; D043823:Taxoids; D000077143:Docetaxel