Department of Pathology, Division of Pathological Neuroscience, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
Int J Mol Sci. 2018 Oct 21;19(10):3267. doi: 10.3390/ijms19103267.
Recent advancement in the field of molecular cancer research has clearly revealed that abnormality of oncogenes or tumor suppressor genes causes tumor progression thorough the promotion of intracellular metabolism. Metabolic reprogramming is one of the strategies for cancer cells to ensure their survival by enabling cancer cells to obtain the macromolecular precursors and energy needed for the rapid growth. However, an orchestration of appropriate metabolic reactions for the cancer cell survival requires the precise mechanism to sense and harness the nutrient in the microenvironment. Mammalian/mechanistic target of rapamycin (mTOR) complexes are known downstream effectors of many cancer-causing mutations, which are thought to regulate cancer cell survival and growth. Recent studies demonstrate the intriguing role of mTOR to achieve the feat through metabolic reprogramming in cancer. Importantly, not only mTORC1, a well-known regulator of metabolism both in normal and cancer cell, but mTORC2, an essential partner of mTORC1 downstream of growth factor receptor signaling, controls cooperatively specific metabolism, which nominates them as an essential regulator of cancer metabolism as well as a promising candidate to garner and convey the nutrient information from the surrounding environment. In this article, we depict the recent findings on the role of mTOR complexes in cancer as a master regulator of cancer metabolism and a potential sensor of nutrients, especially focusing on glucose and amino acid sensing in cancer. Novel and detailed molecular mechanisms that amino acids activate mTOR complexes signaling have been identified. We would also like to mention the intricate crosstalk between glucose and amino acid metabolism that ensures the survival of cancer cells, but at the same time it could be exploitable for the novel intervention to target the metabolic vulnerabilities of cancer cells.
近年来，分子癌症研究领域的进展清楚地表明，癌基因或肿瘤抑制基因的异常通过促进细胞内代谢导致肿瘤进展。代谢重编程是癌细胞确保生存的策略之一，使癌细胞能够获得快速生长所需的大分子前体和能量。然而，为了使癌细胞的生存需要协调适当的代谢反应，需要精确的机制来感知和利用微环境中的营养物质。哺乳动物/雷帕霉素靶蛋白（mTOR）复合物是许多致癌突变的下游效应物，被认为调节癌细胞的存活和生长。最近的研究表明，mTOR 通过癌症中的代谢重编程来实现这一壮举的有趣作用。重要的是，不仅是 mTORC1，它是正常和癌细胞代谢的众所周知的调节剂，而且是 mTORC2，它是生长因子受体信号下游 mTORC1 的重要伙伴，共同控制特定的代谢，这使它们成为癌症代谢的重要调节剂以及从周围环境中获取和传递营养信息的有前途的候选者。在本文中，我们描述了 mTOR 复合物作为癌症代谢的主要调节剂和营养物质的潜在传感器在癌症中的作用的最新发现，特别是重点介绍了癌症中葡萄糖和氨基酸感应的作用。已经确定了氨基酸激活 mTOR 复合物信号的新的详细分子机制。我们还想提到葡萄糖和氨基酸代谢之间复杂的相互作用，这种相互作用确保了癌细胞的存活，但同时也可以利用这种相互作用来针对癌细胞的代谢脆弱性进行新的干预。
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