title: Inhibitory effect of a redox-silent analogue of tocotrienol on hypoxia adaptation in prostate cancer cells.
abstract: Prostate cancer (PCa) is one of the most common cancers in Western countries and acquires a malignant phenotype, androgen-independent growth. PCa under hypoxia often has resistance to chemotherapy and radiotherapy. However, an effective therapy against PCa under hypoxia has not yet been established. In this report, we investigated the inhibitory effect of a redox-silent analogue of tocotrienol on the survival of a human androgen-independent PCa cell line (PC3) under hypoxia. We found that the redox-silent analogue exerted a cytotoxic effect on PC3 cells in a dose-dependent manner irrespective of either hypoxia or normoxia. Moreover, under hypoxia, the analogue dose dependently reduced the protein levels of hypoxia-inducible factor (HIF)-1α and HIF-2α. In addition, a specific inhibitor toward HIF-1α induced cytotoxicity on PC3 cells, whereas selective inhibition of HIF-2α exerted no effect. Furthermore, suppression of HIFs levels by the analogue in hypoxic PC3 cells was closely associated with the inactivation of Fyn, a member of the nonreceptor tyrosine kinase family, as confirmed by the action of a specific inhibitor toward the kinase (PP2). Taken together, these results suggest that the tocotrienol analogue could inhibit the survival of PC3 cells under hypoxia, mainly by the inhibition of Fyn/HIF-1α signaling, and this may lead to the establishment of a new effective therapy for androgen-independent PCa.
authors.affiliation: aGraduate School of Life Sciences bResearch Institute for Life Innovation cDepartment of Food Life Sciences dGraduate School of Food and Nutritional Sciences, Toyo University, Gunma eFaculty of Pharmaceutical Sciences, Setsunan University, Osaka fGraduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Shiozawa
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Sugahara
authors.forename: Kozue
authors.initials: K
authors.lastname: Namiki
authors.forename: Chiaki
authors.initials: C
authors.lastname: Sato
authors.forename: Akira
authors.initials: A
authors.lastname: Ando
authors.forename: Ayami
authors.initials: A
authors.lastname: Sato
authors.forename: Nantiga
authors.initials: N
authors.lastname: Virgona
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yano
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000378:metabolism; D024508:Tocotrienols / Q000494:pharmacology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051076:Proto-Oncogene Proteins c-fyn; D024508:Tocotrienols; D000099162:Endothelial PAS Domain-Containing Protein 1; C501588:6-O-carboxypropyl-alpha-tocotrienol; C497442:HIF1A protein, human; C494957:FYN protein, human