Abstract
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.
Highlights
Proliferating cells require adenosine triphosphate (ATP) as an essential energy source, and intracellular building blocks including nucleotides, fatty acids, and proteins, and a reprogrammed metabolism could serve to support the synthesis of macromolecules [1,2]
We focus on mammalian/mechanistic target of rapamycin complexes, essential regulator of cell proliferation and metabolism, as a potential key player to play a role in sensing nutrients to drive the intracellular tumor-promoting signaling cascade through metabolic reprogramming and epigenetic shift, and a key node which should be therapeutically targeted as a new mode of treatment to interfere with cancer cell metabolism
The findings provide the challenging and promising ideas on the previously unrecognized interaction between glucose and amino acid metabolism through mTOR complex 2 (mTORC2) signaling, which enables cancer cells to promote their survival according to the level of nutrients in the microenvironment
Summary
Proliferating cells require adenosine triphosphate (ATP) as an essential energy source, and intracellular building blocks including nucleotides, fatty acids, and proteins, and a reprogrammed metabolism could serve to support the synthesis of macromolecules [1,2]. Cancer cells are heavily dependent and addicted to glucose metabolism for their survival Amino acids are another major determinant to support cancer cell proliferation. In the process of tumor initiation and progression, cancer cells are exposed to harsh conditions such as hypoxia or nutrient depletion in the tumor microenvironment. To survive in this severe environment, cancer cells must sense and respond to the status of nutrient availability in the extracellular environment to coordinately regulate the gene expression for sustaining the cell proliferation as well as everting the various stress that halts the cell proliferation and induce cell death [9,10,11]. We focus on mammalian/mechanistic target of rapamycin (mTOR) complexes, essential regulator of cell proliferation and metabolism, as a potential key player to play a role in sensing nutrients to drive the intracellular tumor-promoting signaling cascade through metabolic reprogramming and epigenetic shift, and a key node which should be therapeutically targeted as a new mode of treatment to interfere with cancer cell metabolism
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