ASCT2 overexpression is associated with poor survival of OSCC patients and ASCT2 knockdown inhibited growth of glutamine‐addicted OSCC cells

Abstract

BackgroundAlanine‐serine‐cysteine transporter 2 (ASCT2), a major glutamine transporter, is essential for cell growth and tumor development in a variety of cancers. However, the clinicopathological significance and pathological role of ASCT2 in OSCC (oral squamous cell carcinoma) lesions remain unclear.MethodsSections from 89 OSCC patients and 10 paracancerous tissue controls were stained by immunohistochemistry (IHC) to detect the expression of ASCT2, glutaminase, and Ki‐67. Survival analysis was carried out to determine the predictive value of ASCT2 expression using the log‐rank test. Moreover, the critical role of ASCT2 in tumor growth was determined by a series of in vitro and in vivo assays. Cell Counting Kit‐8 (CCK8), Western Blotting (WB), Reactive Oxygen Species (ROS), and Glutathione (GSH) detection were applied to explore the molecular mechanism of ASCT2 involvement in tumor development.ResultsIn OSCC lesions, ASCT2 expression was significantly increased and associated with cell proliferation index (Ki‐67) and GLS expression. Moreover, survival analysis showed that OSCC patients with high ASCT2 expression had lower overall survival (P = 0.0365). In OSCC cell lines, the high level of ASCT2 was inherent and related to the glutamine addiction of tumor cells. In vitro and in vivo functional experiments revealed that targeted silencing of ASCT2 can effectively inhibit OSCC cell proliferation and tumor growth. Mechanistically, targeting ASCT2 knockdown reduced glutamine uptake and intracellular GSH levels, which contribute to the accumulation of ROS and induce apoptosis in OSCC cells.ConclusionASCT2 is a significant factor for predicting overall survival in patients with OSCC, and targeting ASCT2 to inhibit glutamine metabolism may be a promising strategy for OSCC treatment.

The Harmonious Interplay of Amino Acid and Monocarboxylate Transporters Induces the Robustness of Cancer Cells

“…ASCT2 is overexpressed in squamous cell carcinoma, adenocarcinoma, and neuroendocrine lung cancers [ 41 ]. In addition, overexpression of ASCT2 in oral squamous cell carcinoma is positively correlated with poor outcomes [ 42 ]. ASCT2 serves as an obligatory exchanger that imports a sodium-coupled amino acid substrate into cells and exports another sodium-coupled amino acid substrate with 1:1 stoichiometry [ 43 , 44 ].…”

“…System Xc(-) takes up cystine in exchange for glutamate for GSH synthesis, whereas ASCT2 imports glutamine in a cooperative manner [ 28 , 48 ] ( Figure 2 ). Thus, targeted knockdown of ASCT2 inhibits GSH synthesis and induces ferroptosis mediated by the accumulation of intracellular redox stress [ 42 ].…”

Anticancer Properties of Lobetyolin, an Essential Component of Radix Codonopsis (Dangshen)

“…The blockade of glutamine metabolism represents an interesting approach to reduce cancer cell growth, by depriving the cells of the fuel which they need to proliferate [64]. It could be particularly useful to combat aggressive cancers characterized by a large expression of ASCT2, such as advanced laryngeal and oral squamous cell carcinoma [65][66][67]. Such an inhibition of glutamine uptake via down-regulation of ASCT2 in cancer cells has been previously observed with established anticancer drugs, like topotecan used to treat gastric cancer [68].…”

O-GlcNAcylation Coordinates Glutaminolysis by Regulating the Stability and Membrane Trafficking of ASCT2 in Hepatic Stellate Cells

“…ASCT2, an alanine, serine, cysteine-preferring trans-porter, mediated the uptake of glutamine, a conditionally essential amino acid in rapidly proliferating tumor cells. 24 There has been an increased focus on glutamine transport and metabolism as a putative therapeutic target owing to its high expression in many cancers. Previous studies have shown that glutaminolysis is a key component of the metabolic reprogramming of myofibroblasts and fibrosis progression in mice with liver fibrosis, which provides clues for understanding the role of ASCT2 in HSC activation and reversion.…”