Depletion of gamma-glutamylcyclotransferase in cancer cells induces autophagy followed by cellular senescence

American Journal of Cancer Research

Eishi Ashihara¹  Keiko Taniguchi²  Hiromi Ii³  Kengo Matsumura⁴  Susumu Kageyama⁵ 

[1] Department of Clinical Laboratory Medicine, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan;Department of Clinical Oncology, Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashina-ku, Kyoto 607-8414, Japan;Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Shogoin-kawaharacho 54, Sakyoku, Kyoto 606-8507, Japan;Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashina-ku, Kyoto 607-8414, Japan;Department of Urology, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan

关键词: Gamma-glutamylcyclotransferase;    autophagy;    cyclin-dependent kinase inhibitor;    p21WAF1/CIP1;    cellular senescence;    AMPK;    ULK1;    ATG5;    mTORC;    Akt;   

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

Gamma-glutamylcyclotransferase (GGCT) was originally identified as a protein highly expressed in bladder cancer tissues by proteomic analysis, and its higher expression in a variety of cancers compared to normal tissues have been shown. Depletion of GGCT in various cancer cells results in antiproliferative effects both in vitro and in vivo; thus it is considered a promising therapeutic target. Although it has been shown that knockdown of GGCT induces cellular senescence and non-apoptotic cell death, associated with upregulation of cyclin-dependent kinase inhibitors (CDKIs) including p21WAF1/CIP1, the cellular events that follow GGCT depletion are not fully understood. Here, we show that GGCT depletion induced autophagy in MCF7 breast and PC3 prostate cancer cells. Conversely, overexpression of GGCT in NIH3T3 fibroblast under conditions of serum deprivation inhibited autophagy and increased proliferation. Simultaneous knockdown of autophagy related-protein 5, a critical effector of autophagy, along with GGCT in MCF7 and PC3 cells led to significant attenuation of the multiple cellular responses, including upregulation of CDKIs, increased numbers of senescence-associated β-galactosidase positive senescent cells, and growth inhibition. Furthermore, we show that autophagy-promoting signaling cascades including activation of the AMPK-ULK1 pathway and/or inactivation of the mTORC2-Akt pathway were triggered in GGCT-depleted cells. These results indicate that autophagy plays an important role in the growth inhibition of cancer cells caused by GGCT depletion.

【 授权许可】

CC BY-NC