Niu Dun, Xia Yiniu, Qin Xingyu, Zhang Ming, Pan Sichun, Yuan Xuemiao, Tang Guotao, Ai Wenbin, Liang Yuxuan, Li Zhongli, Xie Zhizhong
Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China.
Department of Otorhinolaryngology, The Second Affiliated Hospital of University of South China, Hengyang, Hunan Province, China.
Cell Biol Int. 2025 Jul 31. doi: 10.1002/cbin.70064.
Most evidence obtained to date suggests a pivotal role for lactate in the control of tumor growth and metastasis. However, the precise mechanism by which lactate decreases tumor cell death remains incompletely defined. Here, we report that parthanatos, a kind of poly (ADP-ribose) polymerase-1 (PARP1) dependent but caspase-independent programmed cell death, does occur in two gastric cancer cell lines (MKN28 and MGC803) under glucose-deprived conditions. Lactate prevented the glucose deprivation-induced parthanatos in an acid-independent manner. In addition, glucose deprivation increased intracellular reactive oxygen species (ROS) generation, whereas lactate reduces ROS levels by promoting NADPH generation. AG120, a selective inhibitor of isocitrate dehydrogenase 1 (IDH1) that catalyzes cytosolic NADPH generation, effectively eliminated the effect of lactate on NADPH generation and reversed the protective effect of lactate on glucose deprivation-induced parthanatos. Similar effects were also observed when lactate dehydrogenase B (LDHB) was knocked down. Our findings reveal that lactate prevents glucose deprivation-induced parthanatos in gastric cancer cells by alleviating intracellular oxidative stress, reflecting a new mechanism by which lactate facilitates the adaptation of tumor cells to the nutrient-deficient tumor microenvironment and promotes tumor development.
迄今为止获得的大多数证据表明，乳酸在控制肿瘤生长和转移中起关键作用。然而，乳酸减少肿瘤细胞死亡的确切机制仍未完全明确。在此，我们报告，在葡萄糖缺乏条件下，两种胃癌细胞系（MKN28和MGC803）中确实发生了parthanatos，这是一种聚（ADP-核糖）聚合酶-1（PARP1）依赖性但不依赖半胱天冬酶的程序性细胞死亡。乳酸以不依赖酸的方式阻止了葡萄糖剥夺诱导的parthanatos。此外，葡萄糖剥夺增加了细胞内活性氧（ROS）的产生，而乳酸通过促进烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的产生来降低ROS水平。AG120是催化胞质NADPH产生的异柠檬酸脱氢酶1（IDH1）的选择性抑制剂，它有效消除了乳酸对NADPH产生的影响，并逆转了乳酸对葡萄糖剥夺诱导的parthanatos的保护作用。当敲低乳酸脱氢酶B（LDHB）时也观察到类似的效果。我们的研究结果表明，乳酸通过减轻细胞内氧化应激来阻止葡萄糖剥夺诱导的胃癌细胞parthanatos，这反映了乳酸促进肿瘤细胞适应营养缺乏的肿瘤微环境并促进肿瘤发展的一种新机制。
