title: GPX2 overexpression is involved in cell proliferation and prognosis of castration-resistant prostate cancer.
abstract: There is a need for exploration of new therapeutic strategies that target distinct molecular mechanisms of castration-resistant prostate cancer (CRPC) because its emergence following androgen deprivation therapy is a major clinical problem. In this report, we investigated the role of glutathione peroxidase 2 (GPX2) in CRPC. GPX2 expression was analyzed in rat and human CRPC cells. Next, we determined the proliferation rate and level of reactive oxygen species (ROS) in GPX2-small interfering RNA (siRNA)-transfected CRPC cells. For in vivo analysis, siRNA-transfected cells were subcutaneously implanted into normal and castrated nude mice. Further, immunohistochemical and prognostic analyses of GPX2 were performed using human specimens. Silencing of GPX2 caused significant growth inhibition and increased intracellular ROS in both rat (PCai1) and human (PC3) CRPC cells. Flow cytometry and western blot analyses revealed that the decrease in proliferation rate of the GPX2-silenced cells was due to cyclin B1-dependent G2/M arrest. Furthermore, knockdown of Gpx2 inhibited tumor growth of PCai1 cells in castrated mice. Immunohistochemical analyses indicated that expression of GPX2 was significantly higher in residual cancer foci after neoadjuvant hormonal therapy than in hormone naive cancer foci. Moreover, patients with high GPX2 expression in biopsy specimen had significantly lower prostate-specific antigen recurrence-free survival and overall survival than those with no GPX2 expression. These findings suggest that GPX2 is a prognostic marker in CRPC and affects proliferation of prostate cancer under androgen depletion partially through protection against ROS signaling.
authors.affiliation: Department of Experimental Pathology and Tumor Biology and Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku 467-8601, Nagoya, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Naiki
authors.affiliation: Department of Experimental Pathology and Tumor Biology and ayaito@med.nagoya-cu.ac.jp.
authors.forename: Aya
authors.initials: A
authors.lastname: Naiki-Ito
authors.affiliation: Department of Experimental Pathology and Tumor Biology and.
authors.forename: Makoto
authors.initials: M
authors.lastname: Asamoto
authors.affiliation: Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku 467-8601, Nagoya, Japan.
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Kawai
authors.affiliation: Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku 467-8601, Nagoya, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tozawa
authors.affiliation: Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku 467-8601, Nagoya, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Etani
authors.affiliation: Department of Experimental Pathology and Tumor Biology and.
authors.forename: Shinya
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Experimental Pathology and Tumor Biology and.
authors.forename: Shugo
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Experimental Pathology and Tumor Biology and.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Shirai
authors.affiliation: Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku 467-8601, Nagoya, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kohri
authors.affiliation: Department of Experimental Pathology and Tumor Biology and.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015999:Multivariate Analysis; D009368:Neoplasm Transplantation; D018365:Neoplasm, Residual; D011379:Prognosis; D016016:Proportional Hazards Models; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C117436:GPX2 protein, human; D005979:Glutathione Peroxidase