mTOR Complexes as a Nutrient Sensor for Driving Cancer Progression

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.

Keywords: cancer; mTOR complex; metabolic reprogramming; microenvironment; nutrient sensor.

Figure 1

EGFRvIII controls c-Myc through two interlacing and synergistic mechanisms. EGFRvIII-mTORC1 signaling promotes glycolytic metabolism by activating hnRNPA1-dependent alternative splicing of a Myc-binding partner Delta Max, thereby functionally augmenting the oncogenic activity of c-Myc. Alternatively, EGFR-mTORC2 signaling controls c-Myc transcription, translation and protein level through FoxO acetylation, resulting in the enhancement of metabolic reprogramming. These findings point to the central role of c-Myc in regulating EGFRvIII-activated glycolytic metabolism. EGFRvIII: epidermal growth factor receptor variant III; PI3K: phosphoinositide 3-kinase; mTORC1/2: mammalian/mechanistic target of rapamycin complex 1/2; HDAC: histone deacetylase; hnRNPA1: heterogeneous nuclear ribonucleoprotein A1; Max: myc-associated factor X; FoxO: forkhead box O; Ac: acetyl-group.

Figure 2

Mechanism of mTORC1 activation via Rag proteins by amino acids. mTORC1 is transferred to lysosome from cytosol by promoting heterodimerization of GTP-binding Rag proteins, which work as mediators of amino acid signaling to mTORC1. It is then activated by binding to GTP-bound Rheb on lysosome. Extracellular arginine and leucine activate RagA-RagC heterodimer, GTP-binding RagA, and GDP-binding RagC via amino acid transporter CASTOR1/2 and Sestrin1/2 to transfer mTORC1 to lysosome. Lysosomal arginine also activates Rag heterodimer via lysosomal amino acid transporter SLC38A9.

Figure 3

The function of mTORC2 as a sensor of glucose and amino acid. mTORC2 is activated by glucose through acetylation of Rictor, playing a role as a sensor of glucose. Phosphorylation of Ser26 of xCT by mTORC2 represses its function as glutamate-cystine anti-transporter. Under nutrient (glucose) poor conditions, lower mTORC2 signaling could tilt the balance from proliferation to survival by favoring glutamate efflux, cystine uptake, and glutathione synthesis to protect tumor cells from cellular stress.

Figure 4

Potential molecular therapies targeting mTOR-dependent metabolic reprogramming in cancer cells. xCT: amino acid transport system Xc-; NF-κB: nuclear factor-kappa B; RTK: receptor tyrosine kinase; JAK: Janus kinase; STAT: signal transducers and activators of transcription; ERK: extracellular signal-regulated kinase; S6K1: ribosomal protein S6 kinase 1; 4EBP1: eukaryotic translation initiation factor 4E-binding protein 1; LKB1: liver kinase B1; AMPK: adenosine monophosphate-activated protein kinase; SREBP-1: sterol regulatory element-binding protein 1; LDLR: low density lipoprotein receptor; IDOL: inducible degrader of LDLR; ABCA1: ATP-binding cassette protein A1; LXR: liver X receptor.