Ruiz-Iglesias Ainhoa, Mañes Santos
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB/CSIC), 28049 Madrid, Spain.
Cancers (Basel). 2021 Mar 24;13(7):1488. doi: 10.3390/cancers13071488.
Pyruvate is a key molecule in the metabolic fate of mammalian cells; it is the crossroads from where metabolism proceeds either oxidatively or ends with the production of lactic acid. Pyruvate metabolism is regulated by many enzymes that together control carbon flux. Mitochondrial pyruvate carrier (MPC) is responsible for importing pyruvate from the cytosol to the mitochondrial matrix, where it is oxidatively phosphorylated to produce adenosine triphosphate (ATP) and to generate intermediates used in multiple biosynthetic pathways. MPC activity has an important role in glucose homeostasis, and its alteration is associated with diabetes, heart failure, and neurodegeneration. In cancer, however, controversy surrounds MPC function. In some cancers, MPC upregulation appears to be associated with a poor prognosis. However, most transformed cells undergo a switch from oxidative to glycolytic metabolism, the so-called Warburg effect, which, amongst other possibilities, is induced by MPC malfunction or downregulation. Consequently, impaired MPC function might induce tumors with strong proliferative, migratory, and invasive capabilities. Moreover, glycolytic cancer cells secrete lactate, acidifying the microenvironment, which in turn induces angiogenesis, immunosuppression, and the expansion of stromal cell populations supporting tumor growth. This review examines the latest findings regarding the tumorigenic processes affected by MPC.
丙酮酸是哺乳动物细胞代谢命运中的关键分子;它是代谢走向氧化或最终产生乳酸的十字路口。丙酮酸代谢由许多共同控制碳通量的酶调节。线粒体丙酮酸载体(MPC)负责将丙酮酸从细胞质转运到线粒体基质,在那里它被氧化磷酸化以产生三磷酸腺苷(ATP)并生成用于多种生物合成途径的中间体。MPC活性在葡萄糖稳态中起重要作用,其改变与糖尿病、心力衰竭和神经退行性变有关。然而,在癌症中,MPC的功能存在争议。在某些癌症中,MPC上调似乎与预后不良有关。然而,大多数转化细胞会从氧化代谢转变为糖酵解代谢,即所谓的瓦伯格效应,这在其他可能性中是由MPC功能障碍或下调诱导的。因此,MPC功能受损可能会诱导具有强大增殖、迁移和侵袭能力的肿瘤。此外,糖酵解癌细胞分泌乳酸,使微环境酸化,进而诱导血管生成、免疫抑制以及支持肿瘤生长的基质细胞群体的扩张。本综述探讨了有关MPC影响肿瘤发生过程的最新发现。