Depletion of gamma-glutamylcyclotransferase in cancer cells induces autophagy followed by cellular senescence.
Depletion of gamma-glutamylcyclotransferase in cancer cells induces autophagy followed by cellular senescence.
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发表时间：
2018-04
影响因子：
5.3
通讯作者：
Keiko Taniguchi;Kengo Matsumura;Hiromi Ii;S. Kageyama;E. Ashihara;T. Chano;A. Kawauchi;T. Yoshiki;Susumu Nakata
中科院分区：
文献类型：
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作者：
Keiko Taniguchi;Kengo Matsumura;Hiromi Ii;S. Kageyama;E. Ashihara;T. Chano;A. Kawauchi;T. Yoshiki;Susumu Nakata
γ-谷氨酰环转移酶(GGCT)最初是通过蛋白质组学分析确定在膀胱癌组织中高表达的一种蛋白质，现已发现其在多种肿瘤组织中的表达均高于正常组织。GGCT在多种肿瘤细胞中的缺失在体外和体内都具有抗增殖作用，因此被认为是一个有前途的治疗靶点。尽管已有研究表明，GGCT基因敲除可诱导细胞衰老和非凋亡性细胞死亡，这与细胞周期蛋白依赖性激酶抑制物(CDKI)包括p21WAF1/CIP1上调有关，但GGCT缺失后的细胞事件尚不完全清楚。在这里，我们展示了GGCT耗竭诱导MCF7乳腺癌细胞和PC3前列腺癌细胞的自噬。相反，在血清剥夺条件下，GGCT在NIH3T3成纤维细胞中的过表达抑制了自噬并促进了增殖。在MCF7和PC3细胞中，同时敲除自噬相关蛋白5和GGCT，导致多种细胞反应显著减弱，包括CDKI上调，衰老相关β-半乳糖苷酶阳性衰老细胞数量增加，以及生长抑制。此外，我们还发现，在GGCT缺失的细胞中，包括AMPK-ULK1通路的激活和/或mTORC2-Akt通路的失活在内的促进自噬的信号级联反应被触发。这些结果表明，自噬在GGCT耗竭引起的癌细胞生长抑制中起重要作用。
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.