Inositol Phosphate Recycling Regulates Glycolytic and Lipid Metabolism That Drives Cancer Aggressiveness

Cancer cells possess fundamentally altered metabolism that supports their pathogenic features, which includes a heightened reliance on aerobic glycolysis to provide precursors for synthesis of biomass. We show here that inositol polyphosphate phosphatase 1 (INPP1) is highly expressed in aggressive human cancer cells and primary high-grade human tumors. Inactivation of INPP1 leads to a reduction in glycolytic intermediates that feed into the synthesis of the oncogenic signaling lipid lysophosphatidic acid (LPA), which in turn impairs LPA signaling and further attenuates glycolytic metabolism in a feed-forward mechanism to impair cancer cell motility, invasiveness, and tumorigenicity. Taken together these findings reveal a novel mode of glycolytic control in cancer cells that can serve to promote key oncogenic lipid signaling pathways that drive cancer pathogenicity.癌细胞的代谢发生根本性改变，这种改变支撑其致病特性，其中包括显著增强的有氧糖酵解（aerobic glycolysis）依赖，以获取生物量（biomass）合成所需的前体物质。本研究证实，肌醇多磷酸磷酸酶1（inositol polyphosphate phosphatase 1, INPP1）在侵袭性人类癌细胞及原发性高级别人类肿瘤中呈高表达。INPP1的失活会减少可用于合成致癌信号脂质溶血磷脂酸（lysophosphatidic acid, LPA）的糖酵解中间产物，进而削弱LPA信号通路，并通过前馈机制进一步减弱糖酵解代谢，最终损害癌细胞的迁移、侵袭能力及致瘤性。综上，本研究揭示了癌细胞中一种全新的糖酵解调控模式，该模式可通过激活关键致癌脂质信号通路来推动癌症的致病进程。