Department of Molecular Biology and The Laboratory for Molecular Infection Medicine, Sweden (MIMS), Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden.
Division of Pathophysiology, National Institute of Cholera and Enteric Diseases, Kolkata, India.
Int J Cancer. 2021 Jul 15;149(2):442-459. doi: 10.1002/ijc.33562. Epub 2021 Mar 26.
Colorectal cancer is one of the leading causes of cancer-related death worldwide. The adenomatous polyposis coli (APC) gene is mutated in hereditary colorectal tumors and in more than 80% of sporadic colorectal tumors. APC mutations impair β-catenin degradation, leading to its permanent stabilization and increased transcription of cancer-driving target genes. In colon cancer, impairment of β-catenin degradation leads to its cytoplasmic accumulation, nuclear translocation, and subsequent activation of tumor cell proliferation. Suppressing β-catenin signaling in cancer cells therefore appears to be a promising strategy for new anticancer strategies. Recently, we discovered a novel Vibrio cholerae cytotoxin, motility-associated killing factor A (MakA), that affects both invertebrate and vertebrate hosts. It promotes bacterial survival and proliferation in invertebrate predators but has unknown biological role(s) in mammalian hosts. Here, we report that MakA can cause lethality of tumor cells via induction of apoptosis. Interestingly, MakA exhibited potent cytotoxic activity, in particular against several tested cancer cell lines, while appearing less toxic toward nontransformed cells. MakA bound to the tumor cell surface became internalized into the endolysosomal compartment and induced leakage of endolysosomal membranes, causing cytosolic release of cathepsins and activation of proapoptotic proteins. In addition, MakA altered β-catenin integrity in colon cancer cells, partly through a caspase- and proteasome-dependent mechanism. Importantly, MakA inhibited β-catenin-mediated tumor cell proliferation. Remarkably, intratumor injection of MakA significantly reduced tumor development in a colon cancer murine solid tumor model. These data identify MakA as a novel candidate to be considered in new strategies for development of therapeutic agents against colon cancer.
结直肠癌是全球癌症相关死亡的主要原因之一。腺瘤性结肠息肉病（APC）基因在遗传性结直肠肿瘤和超过 80%的散发性结直肠肿瘤中发生突变。APC 突变会损害β-连环蛋白的降解，导致其永久稳定，并增加致癌靶基因的转录。在结肠癌中，β-连环蛋白降解的损害导致其在细胞质中的积累、核转位，以及随后肿瘤细胞增殖的激活。因此，抑制癌细胞中的β-连环蛋白信号似乎是一种有前途的新抗癌策略。最近，我们发现了一种新型霍乱弧菌细胞毒素，运动相关杀伤因子 A（MakA），它影响无脊椎动物和脊椎动物宿主。它促进了无脊椎动物捕食者中的细菌存活和增殖，但在哺乳动物宿主中具有未知的生物学作用。在这里，我们报告 MakA 通过诱导细胞凋亡导致肿瘤细胞的致死性。有趣的是，MakA 对几种测试的癌细胞系表现出强大的细胞毒性活性，而对非转化细胞的毒性较小。与肿瘤细胞表面结合的 MakA 被内化到内体溶酶体隔室中，并诱导内体溶酶体膜的渗漏，导致胞质中组织蛋白酶的释放和促凋亡蛋白的激活。此外，MakA 改变了结肠癌细胞中的β-连环蛋白完整性，部分通过半胱天冬酶和蛋白酶体依赖性机制。重要的是，MakA 抑制了β-连环蛋白介导的肿瘤细胞增殖。值得注意的是，在结肠癌的小鼠实体瘤模型中，肿瘤内注射 MakA 显著减少了肿瘤的发展。这些数据表明 MakA 是一种新的候选药物，可以考虑用于开发针对结肠癌的治疗药物的新策略。
