Depletion of γ-glutamylcyclotransferase inhibits breast cancer cell growth via cellular senescence induction mediated by CDK inhibitor upregulation

BMC Cancer

Research Article

Keiko Taniguchi¹  Susumu Nakata¹  Kengo Matsumura¹  Hiromi Ii¹  Tatsuhiro Yoshiki²  Eishi Ashihara³  Akihiro Kawauchi⁴  Susumu Kageyama⁴ 

[1] Department of Clinical Oncology, Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashinaku, 607-8414, Kyoto, Japan;Department of Clinical Oncology, Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashinaku, 607-8414, Kyoto, Japan;Department of Urology, Shiga University of Medical Science, Seta Tsukinowa-cho, 520-2192, Otsu, Shiga, Japan;Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashinaku, 607-8414, Kyoto, Japan;Department of Urology, Shiga University of Medical Science, Seta Tsukinowa-cho, 520-2192, Otsu, Shiga, Japan;

关键词: γ-glutamylcyclotransferase;    Cellular senescence;    p21;    p16;    Cell cycle arrest;   

DOI  :  10.1186/s12885-016-2779-y

 received in 2016-02-02, accepted in 2016-09-14,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundChromosome 7 open reading frame 24 (C7orf24) was originally identified as a highly expressed protein in various types of cancer, and later shown to be a γ-glutamylcyclotransferase (GGCT). GGCT depletion in cancer cells has anti-proliferative effects in vitro and in vivo, and it is therefore considered a promising candidate as a therapeutic target. However, the cellular events induced by GGCT depletion remain unclear.MethodsGGCT was depleted by siRNA in MCF7, MDA-MB-231, PC3, A172, Hela, and LNCaP cells. Induction of cellular senescence was evaluated with senescence-associated β-galactosidase (SA-β-Gal) staining. Expression levels of p21WAF1/CIP1 and p16INK4A were assessed by qRT-PCR and Western blotting. Effects of simultaneous double knockdown of p21WAF1/CIP1 and p16INK4A together with GGCT on cell cycle regulation and cell growth was measured by flow cytometry, and trypan blue dye exclusion test.ResultsWe found that GGCT knockdown induces significant cellular senescence in various cancer cells. Cyclin dependent kinase inhibitor p21WAF1/CIP1 and/or p16INK4A were upregulated in all cell lines tested. Simultaneous knockdown of p21WAF1/CIP1 recovered the cell cycle arrest, attenuated cellular senescence induction, and rescued the subsequent growth inhibition in GGCT-silenced MCF7 breast cancer cells. In contrast, in GGCT silenced MDA-MB-231 breast cancer cells, GGCT depletion upregulated p16INK4A, which played a regulatory role in senescence induction, instead of p21WAF1/CIP1.ConclusionsOur findings demonstrate that induction of cellular senescence mediated by the upregulation of cyclin-dependent kinase inhibitors is a major event underlying the anti-proliferative effect of GGCT depletion in breast cancer cells, highlighting the potential of GGCT blockade as a therapeutic strategy to induce cellular senescence.

【 授权许可】

CC BY   
© The Author(s). 2016