STAMP2 increases oxidative stress and is critical for prostate cancer

EMBO Molecular Medicine

Yang Jin²  Ling Wang²  Su Qu²  Xia Sheng²  Alexandr Kristian³  Gunhild M Mælandsmo³  Nora Pällmann²  Erkan Yuca¹  Ibrahim Tekedereli¹  Kivanc Gorgulu¹  Neslihan Alpay¹  Anil Sood⁴  Gabriel Lopez-Berestein¹  Ladan Fazli⁶  Paul Rennie⁶  Bjørn Risberg⁵  Håkon Wæhre⁵  Håvard E Danielsen⁵  Bulent Ozpolat¹ 

[1] Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX, USA;Department of Biosciences, University of Oslo, Oslo, Norway;Department of Tumor Biology, Oslo University Hospital, Oslo, Norway;Gynecological Oncology, MD Anderson Cancer Center, Houston, TX, USA;Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway;The Vancouver Prostate Centre, Vancouver, BC, Canada

关键词: activating transcription factor 4;    iron reductase;    prostate cancer;    reactive oxygen species;    six transmembrane protein of prostate 2;   

DOI  :  10.15252/emmm.201404181

来源: Wiley

【 摘 要 】

Abstract

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.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.