title: CXCR4 is a novel target of cancer chemopreventative isothiocyanates in prostate cancer cells.
abstract: Isothiocyanates (ITCs) derived from cruciferous vegetables, including phenethyl isothiocyanate (PEITC) and sulforaphane (SFN), exhibit in vivo activity against prostate cancer in a xenograft and transgenic mouse model, and thus are appealing for chemoprevention of this disease. Watercress constituent PEITC and SFN-rich broccoli sprout extract are under clinical investigations but the molecular mechanisms underlying their cancer chemopreventive effects are not fully understood. The present study demonstrates that chemokine receptor CXCR4 is a novel target of ITCs in prostate cancer cells. Exposure of prostate cancer cells (LNCaP, 22Rv1, C4-2, and PC-3) to pharmacologically applicable concentrations of PEITC, benzyl isothiocyanate (BITC), and SFN (2.5 and 5 μmol/L) resulted in downregulation of CXCR4 expression. None of the ITCs affected secretion of CXCR4 ligand (stromal-derived factor-1). In vivo inhibition of PC-3 xenograft growth upon PEITC treatment was associated with a significant decrease in CXCR4 protein level. A similar trend was discernible in the tumors from SFN-treated TRAMP mice compared with those of control mice, but the difference was not significant. Stable overexpression of CXCR4 in PC-3 cells conferred significant protection against wound healing, cell migration, and cell viability inhibition by ITCs. Inhibition of cell migration resulting from PEITC and BITC exposure was significantly augmented by RNAi of CXCR4. This study demonstrates, for the first time, that cancer chemopreventive ITCs suppress CXCR4 expression in prostate cancer cells in vitro as well as in vivo. These results suggest that CXCR4 downregulation may be an important pharmacodynamic biomarker of cancer chemopreventative ITCs in prostate adenocarcinoma.
authors.affiliation: Department of Biochemical Science and Technology, Kagoshima University, Kagoshima City, Japan.
authors.forename: Kozue
authors.initials: K
authors.lastname: Sakao
authors.affiliation: Department of Pharmacology and Chemical Biology, and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Avani R
authors.initials: AR
authors.lastname: Vyas
authors.affiliation: Departments of Urology and Pathology, and Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Sreenivasa R
authors.initials: SR
authors.lastname: Chinni
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Ali I
authors.initials: AI
authors.lastname: Amjad
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Rahul
authors.initials: R
authors.lastname: Parikh
authors.affiliation: Department of Pharmacology and Chemical Biology, and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. singhs@upmc.edu.
authors.forename: Shivendra V
authors.initials: SV
authors.lastname: Singh
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D018890:Chemoprevention / Q000379:methods; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics; D013454:Sulfoxides; D023041:Xenograft Model Antitumor Assays
chemical_list: D016588:Anticarcinogenic Agents; C527276:CXCR4 protein, human; D017879:Isothiocyanates; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D013454:Sulfoxides; C058305:phenethyl isothiocyanate; C031403:benzyl isothiocyanate; C016766:sulforaphane