Jiang Mingxia, Qi Ling, Li Lisha, Li Yanjing
Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, 150 Haping St, Nangang District, Harbin, Heilongjiang 150081 P. R. China.
Cell Death Discov. 2020 Oct 28;6:112. doi: 10.1038/s41420-020-00349-0. eCollection 2020.
Apoptosis has long been recognized as a mechanism that kills the cancer cells by cytotoxic drugs. In recent years, studies have proved that pyroptosis can also shrink tumors and inhibit cells proliferation. Both apoptosis and pyroptosis are caspase-dependent programmed cell death pathways. Cysteinyl aspartate specific proteinase-3 (Caspase-3) is a common key protein in the apoptosis and pyroptosis pathways, and when activated, the expression level of tumor suppressor gene Gasdermin E (GSDME) determines the mechanism of tumor cell death. When GSDME is highly expressed, the active caspase-3 cuts it and releases the N-terminal domain to punch holes in the cell membrane, resulting in cell swelling, rupture, and death. When the expression of GSDME is low, it will lead to the classical mechanism of tumor cell death, which is apoptosis. More interestingly, researchers have found that GSDME can also be located upstream of caspase-3, connecting extrinsic, and intrinsic apoptotic pathways. Then, promoting caspase-3 activation, and forming a self-amplifying feed-forward loop. GSDME-mediated pyroptosis is correlated with the side effects of chemotherapy and anti-tumor immunity. This article mainly reviews the caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer, to provide new strategies and targets for cancer treatment.
长期以来，细胞凋亡一直被认为是一种通过细胞毒性药物杀死癌细胞的机制。近年来，研究证明细胞焦亡也可以使肿瘤缩小并抑制细胞增殖。细胞凋亡和细胞焦亡都是半胱天冬酶依赖性程序性细胞死亡途径。半胱氨酸天冬氨酸特异性蛋白酶-3（Caspase-3）是细胞凋亡和细胞焦亡途径中共同的关键蛋白，激活后，肿瘤抑制基因Gasdermin E（GSDME）的表达水平决定肿瘤细胞的死亡机制。当GSDME高表达时，活性Caspase-3将其切割并释放N端结构域，在细胞膜上打孔，导致细胞肿胀、破裂和死亡。当GSDME表达低时，将导致肿瘤细胞死亡的经典机制，即细胞凋亡。更有趣的是，研究人员发现GSDME也可以位于Caspase-3的上游，连接外源性和内源性凋亡途径。然后，促进Caspase-3激活，并形成一个自我放大的前馈环。GSDME介导的细胞焦亡与化疗副作用和抗肿瘤免疫相关。本文主要综述Caspase-3/GSDME信号通路作为癌症中细胞凋亡和细胞焦亡之间的开关，为癌症治疗提供新的策略和靶点。
