Abstract
Simple SummaryASCT2 and LAT1 are amino acid transporters whose impact in cancer has been explored throughout the years. They have been associated with most currently accepted hallmarks of cancer, thus the aim of this review is to report the impact of these transporters in this disease, as well as their clinical significance and applications. ASCT2 and LAT1 have been identified as prognostic factors and potentially as therapeutic targets. In conclusion, the study and development of new inhibitors for these amino acid transporters constitutes a promising approach towards the improvement of cancer treatment and prognosis.The role of the amino acid transporters ASCT2 and LAT1 in cancer has been explored throughout the years. In this review, we report their impact on the hallmarks of cancer, as well as their clinical significance. Overall, both proteins have been associated with cell death resistance through dysregulation of caspases and sustainment of proliferative signaling through mTOR activation. Furthermore, ASCT2 appears to play an important role in cellular energetics regulation, whereas LAT1 expression is associated with angiogenesis and invasion and metastasis activation. The molecular impact of these proteins on the hallmarks of cancer translates into various clinical applications and both transporters have been identified as prognostic factors in many types of cancer. Concerning their role as therapeutic targets, efforts have been undertaken to synthesize competitive or irreversible ASCT2 and LAT1 inhibitors. However, JHP203, a selective inhibitor of the latter, is, to the best of our knowledge, the only compound included in a Phase 1 clinical trial. In conclusion, considering the usefulness of ASCT2 and LAT1 in a variety of cancer-related pathways and cancer therapy/diagnosis, the development and testing of novel inhibitors for these transporters that could be evaluated in clinical trials represents a promising approach to cancer prognosis improvement.
Highlights
Protein synthesis is essential to fuel the metabolic needs of cancer cell growth and relies on the maintenance of a homeostatic concentration of cytosolic amino acids, the primary source of cellular nitrogen [1,2,3]
LAT1 has been detected in RERF-LC-MA lung small cell carcinoma cells, leukemia cell lines, T24 bladder carcinoma cells, and HeLa uterine cervical carcinoma cells and its expression has been correlated with the size of metastatic distant tumors in rats, being suggested as a potential therapeutic target for many cancers [3]
Ren et al [104] have shown that neuroblastomas with amplification of the MYCN gene, which is associated with high levels of the N-Myc protein, rely on high amounts of glutamine to sustain cell viability, the tricarboxylic acid (TCA) cycle and biosynthetic activities and that those high amounts are supported by ASCT2 activation
Summary
Protein synthesis is essential to fuel the metabolic needs of cancer cell growth and relies on the maintenance of a homeostatic concentration of cytosolic amino acids, the primary source of cellular nitrogen [1,2,3]. During the development of cancer and other metabolic diseases, proteins that confer growth and survival advantages, like amino acid transporters, are often overexpressed [3]. These transporters can be found in the plasma membrane or intracellular compartments such as the mitochondria, late endos40omes, lysosomes, and the Golgi apparatus [5]. This review will cover the function of ASCT2 and LAT1 transporters, their involvement in cancer, and their association with the hallmarks of cancer It will address the clinical significance of both transporters, including their prognostic value and implication in therapy
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