Chen Fangquan, Tang Hu, Lin Junhao, Xiang Limin, Lu Yanjiao, Kang Rui, Tang Daolin, Liu Jiao
DAMP Laboratory, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510150, China.
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, United States.
Carcinogenesis. 2024 Dec 30;45(12):953-964. doi: 10.1093/carcin/bgae045.
Alkaliptosis, a form of regulated cell death, is characterized by lysosomal dysfunction and intracellular pH alkalinization. The pharmacological induction of alkaliptosis using the small molecule compound JTC801 has emerged as a promising anticancer strategy in various types of cancers, particularly pancreatic ductal adenocarcinoma (PDAC). In this study, we investigate a novel mechanism by which macropinocytosis, an endocytic process involving the uptake of extracellular material, promotes resistance to alkaliptosis in human PDAC cells. Through lipid metabolomics analysis and functional studies, we demonstrate that the inhibition of alkaliptosis by fatty acids, such as oleic acid, is not dependent on endogenous synthetic pathways but rather on exogenous uptake facilitated by macropinocytosis. Consequently, targeting macropinocytosis through pharmacological approaches (e.g. using EIPA or EHoP-016) or genetic interventions (e.g. RAC1 knockdown) effectively enhances JTC801-induced alkaliptosis in human PDAC cells. These findings provide compelling evidence that the modulation of macropinocytosis can increase the sensitivity of cancer cells to alkaliptosis inducers.
碱中毒性坏死是一种程序性细胞死亡形式，其特征是溶酶体功能障碍和细胞内pH值碱化。使用小分子化合物JTC801对碱中毒性坏死进行药理学诱导已成为各种癌症，特别是胰腺导管腺癌（PDAC）中一种有前景的抗癌策略。在本研究中，我们研究了一种新机制，即巨胞饮作用（一种涉及摄取细胞外物质的内吞过程）促进人PDAC细胞对碱中毒性坏死的抗性。通过脂质代谢组学分析和功能研究，我们证明脂肪酸（如油酸）对碱中毒性坏死的抑制不依赖于内源性合成途径，而是依赖于巨胞饮作用促进的外源性摄取。因此，通过药理学方法（如使用EIPA或EHoP-016）或基因干预（如敲低RAC1）靶向巨胞饮作用可有效增强JTC801诱导的人PDAC细胞碱中毒性坏死。这些发现提供了令人信服的证据，表明巨胞饮作用的调节可增加癌细胞对碱中毒性坏死诱导剂的敏感性。
