Glutaminolysis and carcinogenesis of oral squamous cell carcinoma

Abstract

Glutaminolysis is a crucial factor for tumor metabolism in the carcinogenesis of several tumors but has not been clarified for oral squamous cell carcinoma (OSCC) yet. Expression of glutaminolysis-related solute carrier family 1, member 5 (SLC1A5)/neutral amino acid transporter (ASCT2), glutaminase (GLS), and glutamate dehydrogenase (GLDH) was analyzed in normal oral mucosa (n = 5), oral precursor lesions (simple hyperplasia, n = 11; squamous intraepithelial neoplasia, SIN I-III, n = 35), and OSCC specimen (n = 42) by immunohistochemistry. SLC1A5/ASCT2 and GLS were significantly overexpressed in the carcinogenesis of OSCC compared with normal tissue, while GLDH was weakly detected. Compared with SIN I-III SLC1A5/ASCT2 and GLS expression were significantly increased in OSCC. GLDH expression did not significantly differ from SIN I-III compared with OSCC. This study shows the first evidence of glutaminolysis-related SLC1A5/ASCT2, GLS, and GLDH expression in OSCC. The very weak GLDH expression indicates that glutamine metabolism is rather related to nucleotide or protein/hexosamine biosynthesis or to the function as an antioxidant (glutathione) than to energy production or generation of lactate through entering the tricarboxylic acid cycle. Overcoming glutaminolysis by targeting c-Myc oncogene (e.g. by natural compounds) and thereby cross-activation of mammalian target of rapamycin complex 1 or SLC1A5/ASCT2, GLS inhibitors may be a useful strategy to sensitize cancer cells to common OSCC cancer therapies.

Targeting thiamine-dependent enzymes for metabolic therapies in oral squamous cell carcinoma?

“…It has been postulated that several pathways of carcinogenesis are associated with metabolic phases of transformation in tumor cells, which can be regarded as an integrated metabolic ecosystem [1,3,4]. Our recent studies in OSCCs demonstrated glycolysis, glutaminolysis, and mitochondrial oxidative phosphorylation (OXPHOS) to play major roles in tumor metabolism [1,[4][5][6]. Moreover, the pentose phosphate pathway (PPP) [7] is a crucial factor for survival of OSCC tumor cells [8,9].…”

“…Our recent studies [1,4] demonstrated glycolysis, mitochondrial OXPHOS, and glutaminolysis as important cancer metabolism pathways for oral carcinogenesis. However, analysis of thiamine-dependent enzymes within the network of these pathways as indication for 'metabolic therapies' [22] in OSCC has not been reported yet.…”

“…TKT is a cytosolic enzyme and is regarded as a key player in the PPP, a major route for the biosynthesis of nucleotides [8,9]. Moreover, TKT-like 1 isoform TKTL1 has been shown to be responsible for generation of glutathione as an antioxidant of tumor cells (production of nicotinamide adenine dinucleotide phosphate, NADPH) linking the PPP with glutaminolysis and fatty acid synthesis [4,12,13].…”

<p>Low-Concentration PTX And RSL3 Inhibits Tumor Cell Growth Synergistically By Inducing Ferroptosis In Mutant p53 Hypopharyngeal Squamous Carcinoma</p>

“…26 Dependent on NADPH/H+, polyunsaturated fatty acid metabolism, and the mevalonate and glutaminolysis, metabolic pathways have been implicated in ferroptosis. [27][28][29][30][31] Meanwhile, exploitation of ferroptosis in response to specific compounds is also attracting strategy in cancer therapy. Our study primarily showed the GPX4 overexpression did not inhibit ferroptotic cell death induced by RSL3 and low-concentration PTX.…”

SLC1A5 Silencing Inhibits Esophageal Cancer Growth via Cell Cycle Arrest and Apoptosis

“…previously demonstrated that HER2-type breast cancer expresses the highest SLC1A5 levels evaluated to date using immunohistochemistry. SLC1A5 expression is also associated with non-small cell lung cancer [10], lacrimal gland adenoid cystic carcinoma [11], oral squamous cell carcinoma [12], pancreatic ductal carcinoma [13], tongue cancer [14], and colorectal cancer [15]. Notably, while recent research has shown that SLC1A5 expression is increased in esophageal carcinoma [16], the biological significance of SLC1A5 in the development and/or progression of esophageal cancer has not been reported.…”