glutaminase and Squamous-Cell-Carcinoma-of-Head-and-Neck

Radiotherapy (RT) is one of the primary treatments of head and neck squamous cell carcinoma (HNSCC), which has a high-risk of locoregional failure (LRF). Presently, there is no reliable predictive biomarker of radioresistance in HNSCC. Here, we found that mutations in NFE2L2, which encodes Nrf2, are associated with a significantly higher rate of LRF in patients with oral cavity cancer treated with surgery and adjuvant (chemo)radiotherapy but not in those treated with surgery alone. Somatic mutation of NFE2L2 led to Nrf2 activation and radioresistance in HNSCC cells. Tumors harboring mutant Nrf2E79Q were substantially more radioresistant than tumors with wild-type Nrf2 in immunocompetent mice, whereas the difference was diminished in immunocompromised mice. Nrf2E79Q enhanced radioresistance through increased recruitment of intratumoral polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) and reduction of M1-polarized macrophages. Treatment with the glutaminase inhibitor CB-839 overcame the radioresistance induced by Nrf2E79Q or Nrf2E79K. RT increased expression of PMN-MDSC-attracting chemokines, including CXCL1, CXLC3, and CSF3, in Nrf2E79Q-expressing tumors via the TLR4, which could be reversed by CB-839. This study provides insights into the impact of NFE2L2 mutations on radioresistance and suggests that CB-839 can increase radiosensitivity by switching intratumoral myeloid cells to an antitumor phenotype, supporting clinical testing of CB-839 with RT in HNSCC with NFE2L2 mutations.. NFE2L2 mutations are predictive biomarkers of radioresistance in head and neck cancer and confer sensitivity to glutaminase inhibitors to overcome radioresistance.

Topics: Animals; Carcinoma, Squamous Cell; Glutaminase; Head and Neck Neoplasms; Humans; Mice; Mutation; Myeloid-Derived Suppressor Cells; NF-E2-Related Factor 2; Radiation Tolerance; Squamous Cell Carcinoma of Head and Neck

Various circular RNAs (circRNAs) have been shown to exert vital functions in tongue squamous cell carcinoma (TSCC). However, their roles in TSCC progression remain to be elucidated. This research aimed to investigate the role and mechanism of hsa_circ_0000003 (circ_0000003) in TSCC progression. Here, we found that circ_0000003 expression was upregulated in TSCC tissues and cell lines, and high circ_0000003 expression was correlated with advanced TNM stage, increased tumor size and poor patient survival. Circ_0000003 was revealed to facilitate cell proliferation, migration and invasion of TSCC cells. Mechanistically, we found that circ_0000003 acted as a competing endogenous RNA (ceRNA) that sponged miR‑330‑3p, thereby elevating glutaminase (GLS) expression. Accordingly, cell invasion, migration, glutamine consumption, α‑ketoglutarate (α‑KG) production and ATP production were significantly decreased by circ_0000003 knockdown in TSCC cells, and these effects were reversed by miR‑330‑3p inhibition. In conclusion, circ_0000003 facilitates TSCC cell proliferation, migration, invasion and glutamine catabolism by regulating the miR‑330‑3p/GLS pathway.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Gene Knockdown Techniques; Glutaminase; Glutamine; Humans; MicroRNAs; Neoplasm Invasiveness; RNA, Circular; Squamous Cell Carcinoma of Head and Neck; Tongue; Tongue Neoplasms; Up-Regulation

Alanine-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.. Sections 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.. In 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.. ASCT2 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.

Topics: Aged; Amino Acid Transport System ASC; Animals; Cell Line, Tumor; Cell Proliferation; Female; Gene Knockdown Techniques; Glutaminase; Glutamine; Glutathione; Humans; Immunohistochemistry; Male; Mice; Mice, Nude; Middle Aged; Minor Histocompatibility Antigens; Mouth Neoplasms; Neoplasm Transplantation; Reactive Oxygen Species; Squamous Cell Carcinoma of Head and Neck