Alves Sara, Santos-Pereira Cátia, Oliveira Cláudia S F, Preto Ana, Chaves Susana R, Côrte-Real Manuela
CBMA-Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, 4710-057 Braga, Portugal.
Biomolecules. 2024 Apr 12;14(4):473. doi: 10.3390/biom14040473.
Colorectal cancer (CRC) is a leading cause of death worldwide. Conventional therapies are available with varying effectiveness. Acetate, a short-chain fatty acid produced by human intestinal bacteria, triggers mitochondria-mediated apoptosis preferentially in CRC but not in normal colonocytes, which has spurred an interest in its use for CRC prevention/therapy. We previously uncovered that acetate-induced mitochondrial-mediated apoptosis in CRC cells is significantly enhanced by the inhibition of the lysosomal protease cathepsin D (CatD), which indicates both mitochondria and the lysosome are involved in the regulation of acetate-induced apoptosis. Herein, we sought to determine whether mitochondrial function affects CatD apoptotic function. We found that enhancement of acetate-induced apoptosis by CatD inhibition depends on oligomycin A-sensitive respiration. Mechanistically, the potentiating effect is associated with an increase in cellular and mitochondrial superoxide anion accumulation and mitochondrial mass. Our results provide novel clues into the regulation of CatD function and the effect of tumor heterogeneity in the outcome of combined treatment using acetate and CatD inhibitors.
结直肠癌（CRC）是全球主要的死亡原因之一。现有的传统疗法疗效各异。乙酸盐是人体肠道细菌产生的一种短链脂肪酸，它优先在结直肠癌细胞中引发线粒体介导的细胞凋亡，而在正常结肠细胞中则不会，这激发了人们对其用于预防/治疗结直肠癌的兴趣。我们之前发现，通过抑制溶酶体蛋白酶组织蛋白酶D（CatD），乙酸盐诱导的结直肠癌细胞线粒体介导的细胞凋亡会显著增强，这表明线粒体和溶酶体都参与了乙酸盐诱导的细胞凋亡的调控。在此，我们试图确定线粒体功能是否会影响CatD的凋亡功能。我们发现，通过抑制CatD增强乙酸盐诱导的细胞凋亡取决于寡霉素A敏感的呼吸作用。从机制上讲，这种增强作用与细胞和线粒体超氧阴离子积累以及线粒体质量的增加有关。我们的研究结果为CatD功能的调控以及肿瘤异质性对使用乙酸盐和CatD抑制剂联合治疗结果的影响提供了新线索。
