Given that cancer cells exhibit the aerobic glycolysis termed “Warburg effect”, metabolites derived from glycolysis are important materials for amino acid production and macromolecule synthesis, which is required for robust tumor growth and proliferation. This review highlights the pathological significance of amino acid transporters including xCT, ASCT2, and LAT1, as well as monocarboxylate transporters (MCTs) such as MCT1 and MCT4. Thus, increasing investigations have demonstrated the feasibility of amino acid transporters as a component of anti-cancer therapy. The expression levels of amino acid transporters are closely associated with tumor size, pathological grade and distant metastasis. Proliferating cancer stem-like cells are likely to exhibit additional metabolic reprogramming, concomitant with the upregulation of mitochondrial oxidative phosphorylation (OXPHOS)-related molecules.ĭue to the rapid proliferation, cancer cells have increased demand for amino acids in maintaining one-carbon metabolism, signal pathway, as well as the synthesis of nucleotide and protein. For example, while non-cancer stem-like cells are susceptible to chemotherapy and undergo apoptosis, released cytokine prostaglandin E 2 (PGE 2) awakens the dormant cancer stem-like cells localized in the niche, which is the favorable microenvironment. Cancer stem cells have a robust phenotype, encompassing several characteristics such as a slow cell cycle, the ability to detoxify or promote the efflux of anti-cancer drugs, resistance to redox stress, and a rapid response to genotoxic damage-all of which contribute to the acquisition of chemoresistance. Increasing evidence strongly suggests that metabolic reprogramming is crucial for cancer stem-like cells to maintain unlimited self-renewal potential and hyper-adaptation to drastic changes in the tumor microenvironment. Some of the most striking alterations of tumor cellular bioenergetics include activation of glycolysis, increase in glutaminolytic flux, upregulation of amino acid transporters and lipid metabolism, enhancement of mitochondrial biogenesis, and activation of the pentose phosphate pathway and macromolecule biosynthesis. Hanahan and Weinberg in their review article published in 2011. Metabolic reprogramming specific to cancer cells is one of the ten cancer hallmarks described by Drs.

This review highlights the pathological function and therapeutic targets of transporters including xCT, ASCT2, LAT1, and MCT. Therefore, metabolic reprogramming based on these transporters may be a promising therapeutic target. Differential expression patterns of transporters cause functional intratumoral heterogeneity leading to the therapeutic resistance. Monocarboxylate transporters (MCTs) mediate metabolic symbiosis, by which lactate in cancer cells under hypoxia is exported through MCT4 and imported by MCT1 in less hypoxic regions, where it is used as an oxidative metabolite. Metabolic reprogramming of glutamine occurs often in cancer cells and manifests as ASCT2-mediated glutamine addiction. LAT1 is overexpressed in various malignancies and positively correlated with poor clinical outcome. mTOR signaling regulated by LAT1 is a sensor of dynamic alterations in the nutrient tumor microenvironment. Inhibiting the interaction between LAT1 and CD98 heavy chain prevents activation of the mammalian target of rapamycin (mTOR) complex 1 by glutamine and leucine. CD44 variant, a cancer stem-like cell marker, stabilizes the xCT antiporter at the cellular membrane, and tumor cells positive for xCT and/or ASCT2 are susceptible to sulfasalazine, a system Xc(-) inhibitor. Amino acid transporters characterized by xCT (SLC7A11), ASCT2 (SLC1A5), and LAT1 (SLC7A5) function in the uptake and export of amino acids such as cystine and glutamine, thereby regulating glutathione synthesis, autophagy, and glutaminolysis. The fine regulation of expression levels of amino acid and monocarboxylate transporters enables cancer cells to exhibit the metabolic reprogramming that is responsible for therapeutic resistance. There is a growing body of evidence that metabolic reprogramming contributes to the acquisition and maintenance of robustness associated with malignancy.

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