Journal Article

STAMP2 increases oxidative stress and is critical for prostate cancer

Lopez‐Berestein, Gabriel, Pällmann, Nora, Wæhre, Håkon, Qu, Su, Gorgulu, Kivanc, Ozpolat, Bulent, Alpay, Neslihan, Rennie, Paul, Wang, Ling, Sood, Anil, Fazli, Ladan, Sheng, Xia, Kristian, Alexandr, Tekedereli, Ibrahim, Risberg, Bjørn, Jin, Yang, Yuca, Erkan, Mælandsmo, Gunhild M, Saatcioglu, Fahri, Danielsen, Håvard E

2015

Overview

The six transmembrane protein of prostate 2 ( STAMP2) is an androgen‐regulated gene whose mRNA expression is increased in prostate cancer (PCa). Here, we show that STAMP2 protein expression is increased in human PCa compared with benign prostate that is also correlated with tumor grade and treatment response. We also show that STAMP2 significantly increased reactive oxygen species (ROS) in PCa cells through its iron reductase activity which also depleted NADPH levels. Knockdown of STAMP2 expression in PCa cells inhibited proliferation, colony formation, and anchorage‐independent growth, and significantly increased apoptosis. Furthermore, STAMP2 effects were, at least in part, mediated by activating transcription factor 4 (ATF4), whose expression is regulated by ROS. Consistent with in vitro findings, silencing STAMP2 significantly inhibited PCa xenograft growth in mice. Finally, therapeutic silencing of STAMP2 by systemically administered nanoliposomal siRNA profoundly inhibited tumor growth in two established preclinical PCa models in mice. These data suggest that STAMP2 is required for PCa progression and thus may serve as a novel therapeutic target. Synopsis The androgen‐regulated transmembrane protein STAMP2 is shown to be a critical factor in prostate cancer progression and a possible therapeutic target. STAMP2 regulates cell proliferation by increasing ROS, which in turn activate ATF4 expression. During prostate cancer progression, STAMP2 expression is deregulated and correlated with tumor grade and response to treatment. STAMP2 knockdown inhibits cell proliferation, colony formation, and anchorage‐independent growth, while significantly increasing apoptosis. STAMP2 significantly increases ROS through its iron reductase activity and depletes NADPH levels resulting in ATF4 expression. Therapeutic STAMP2 silencing by systemically administered nanoliposomal siRNA profoundly inhibits tumor growth in preclinical prostate cancer models suggesting that STAMP2 may serve as a novel therapeutic target. Graphical Abstract The androgen‐regulated transmembrane protein STAMP2 is shown to be a critical factor in prostate cancer progression and a possible therapeutic target. STAMP2 regulates cell proliferation by increasing ROS, which in turn activate ATF4 expression.

• Publisher: Nature Publishing Group UK,John Wiley & Sons, Inc,EMBO Press,BlackWell Publishing Ltd,Springer Nature
• Subject: Activating transcription factor 4 / Activating Transcription Factor 4 - metabolism / Androgens / Animal models / Animals / Apoptosis / Cell growth / Cell Line, Tumor / Cell proliferation / Comparative analysis / Disease Models, Animal / EMBO03 / EMBO45 / Experiments / FMN Reductase - genetics / FMN Reductase - metabolism / Gene expression / Gene Expression Regulation / Gene Knockdown Techniques / Genes / Health aspects / Humans / iron reductase / Male / Membrane Proteins - genetics / Membrane Proteins - metabolism / Mice / NADP / Oxidative Stress / Oxidoreductases - genetics / Oxidoreductases - metabolism / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / Reactive Oxygen Species / Reductase / Research Article / siRNA / six transmembrane protein of prostate 2 / Skin cancer / Therapeutic applications / Transplantation, Heterologous / Tumors / Variance analysis / Xenografts