The Importance of Mitochondrial Pyruvate Carrier in Cancer Cell Metabolism and Tumorigenesis.
The Importance of Mitochondrial Pyruvate Carrier in Cancer Cell Metabolism and Tumorigenesis.
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线粒体丙酮酸载体在癌细胞代谢和肿瘤发生中的作用。
DOI：
10.3390/cancers13071488
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发表时间：
2021-03-24
期刊：
影响因子：
5.2
通讯作者：
Mañes S
中科院分区：
文献类型：
--
作者：
Ruiz-Iglesias A;Mañes S
癌细胞特有的代谢特征是葡萄糖在糖酵解过程中大量分解代谢，即使在有氧条件下也是如此--即所谓的华宝效应。虽然糖酵解在能量上是不利的，但它为维持恶性细胞的无限生长提供了“积木”。糖酵解异常也是肿瘤环境中乳酸堆积和酸中毒的原因，这会导致缺氧和免疫抑制。癌细胞用来增加糖酵解流动的机制之一是对形成线粒体丙酮酸载体(MPC)复合体的蛋白质的负调控，该复合体将丙酮酸输送到线粒体基质中，在三羧酸(TCA)循环中进行代谢。有证据表明，肿瘤细胞中MPC的下调影响肿瘤发生的许多方面，包括癌细胞的内在属性(增殖、侵袭力、干性、治疗抵抗力)和外在属性(血管生成、抗肿瘤免疫活性)。在许多癌症中，但不是全部，MPC表达下调与较低的存活率有关。因此，MPC调节是解决肿瘤糖酵解的核心。丙酮酸是哺乳动物细胞代谢命运的关键分子；它是代谢的十字路口，代谢要么以氧化方式进行，要么以乳酸的产生结束。丙酮酸的代谢受到许多酶的调节，这些酶共同控制着碳流。线粒体丙酮酸载体(MPC)负责将丙酮酸从胞浆输入线粒体基质，在线粒体基质中氧化磷酸化产生三磷酸腺苷(ATP)，并产生用于多种生物合成途径的中间体。MPC活性在血糖稳态中起重要作用，它的改变与糖尿病、心力衰竭和神经退行性变有关。然而，在癌症中，围绕MPC功能的争议。在某些癌症中，MPC上调似乎与预后不良有关。然而，大多数转化的细胞经历了从氧化代谢到糖酵解代谢的转换，即所谓的Warburg效应，除了其他可能性外，这是由MPC故障或下调引起的。因此，MPC功能受损可能诱发具有较强增殖、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、免疫抑制和支持肿瘤生长的基质细胞群的扩张。本文综述了有关MPC影响肿瘤发生过程的最新研究结果。
The characteristic metabolic hallmark of cancer cells is the massive catabolism of glucose by glycolysis, even under aerobic conditions—the so-called Warburg effect. Although energetically unfavorable, glycolysis provides “building blocks” to sustain the unlimited growth of malignant cells. Aberrant glycolysis is also responsible for lactate accumulation and acidosis in the tumor milieu, which fosters hypoxia and immunosuppression. One of the mechanisms used by cancer cells to increase glycolytic flow is the negative regulation of the proteins that conform the mitochondrial pyruvate carrier (MPC) complex, which transports pyruvate into the mitochondrial matrix to be metabolized in the tricarboxylic acid (TCA) cycle. Evidence suggests that MPC downregulation in tumor cells impacts many aspects of tumorigenesis, including cancer cell-intrinsic (proliferation, invasiveness, stemness, resistance to therapy) and -extrinsic (angiogenesis, anti-tumor immune activity) properties. In many cancers, but not in all, MPC downregulation is associated with poor survival. MPC regulation is therefore central to tackling glycolysis in tumors. 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.
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影响因子：
4.8
作者：
Becker, Holger M.;Deitmer, Joachim W.
通讯作者：
Deitmer, Joachim W.
DOI：
10.1016/0005-2736(74)90325-3
发表时间：
1974-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
BAKKER, EP;VANDAM, K
通讯作者：
VANDAM, K
影响因子：
4.3
作者：
Colombini, M
通讯作者：
Colombini, M
影响因子：
4.8
作者：
Becker, HM;Hirnet, D;Deitmer, JW
通讯作者：
Deitmer, JW
影响因子：
10.9
作者：
Carmona-Rodriguez, Lorena;Martinez-Rey, Diego;Manes, Santos
通讯作者：
Manes, Santos