Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
Mutat Res Rev Mutat Res. 2021 Jan-Jun;787:108366. doi: 10.1016/j.mrrev.2021.108366. Epub 2021 Jan 18.
Breast cancer (BC) is a heterogeneous cancer with multiple subtypes affecting women worldwide. Triple-negative breast cancer (TNBC) is a prominent subtype of BC with poor prognosis and an aggressive phenotype. Recent understanding of metabolic reprogramming supports its role in the growth of cancer cells and their adaptation to their microenvironment. The Warburg effect is characterized by the shift from oxidative to reductive metabolism and external secretion of lactate. The Warburg effect prevents the use of the required pyruvate in the tricarboxylic acid (TCA) cycle progressing through pyruvate dehydrogenase inactivation. Therefore, it is a major regulatory mechanism to promote glycolysis and disrupt the TCA cycle. Glutamine (Gln) can supply the complementary energy for cancer cells. Additionally, it is the main substrate to support bioenergetics and biosynthetic activities in cancer cells and plays a vital role in a wide array of other processes such as ferroptosis. Thus, the switching of glucose to Gln in the TCA cycle toward reductive Gln metabolism is carried out by hypoxia-inducible factors (HIFs) conducted through the Warburg effect. The literature suggests that the addiction of TNBC to Gln could facilitate the proliferation and invasiveness of these cancers. Thus, Gln metabolism inhibitors, such as CB-839, could be applied to manage the carcinogenic properties of TNBC. Such inhibitors, along with conventional chemotherapy agents, can potentially improve the efficiency and efficacy of TNBC treatment. In this review, we discuss the associations between glucose and Gln metabolism and control of cancer cell growth from the perspective that Gln metabolism inhibitors could improve the current chemotherapy drug effects.
乳腺癌（BC）是一种具有多种亚型的异质性癌症，影响着全世界的女性。三阴性乳腺癌（TNBC）是 BC 的一个突出亚型，预后不良，表现出侵袭性表型。最近对代谢重编程的认识支持其在癌细胞生长及其适应微环境中的作用。沃伯格效应的特征是从氧化代谢向还原性代谢和乳酸的外部分泌转移。沃伯格效应阻止了三羧酸（TCA）循环中所需丙酮酸的使用，丙酮酸通过丙酮酸脱氢酶失活进行。因此，它是促进糖酵解和破坏 TCA 循环的主要调节机制。谷氨酰胺（Gln）可以为癌细胞提供补充能量。此外，它是支持癌细胞生物能量学和生物合成活性的主要底物，并在广泛的其他过程中发挥重要作用，如铁死亡。因此，通过缺氧诱导因子（HIFs）通过沃伯格效应进行的 TCA 循环中葡萄糖向还原性 Gln 代谢的转换是由 Gln 完成的。文献表明，TNBC 对 Gln 的依赖可能促进这些癌症的增殖和侵袭性。因此，Gln 代谢抑制剂，如 CB-839，可以用于控制 TNBC 的致癌特性。这些抑制剂与传统化疗药物联合使用，有可能提高 TNBC 治疗的效率和效果。在这篇综述中，我们从 Gln 代谢抑制剂可以提高现有化疗药物效果的角度，讨论了葡萄糖和 Gln 代谢与控制癌细胞生长之间的关系。
