Radiotherapy is now widely used as a part of multidisciplinary treatment approaches for advanced laryngeal carcinoma and preservation of laryngeal function. However, the mechanism of the radioresistance is still unclear. Some studies have revealed that the Warburg effect promotes the radioresistance of various malignant tumors, including laryngeal carcinoma. Among the regulators involved in the Warburg effect, hexokinase-II (HK-II) is a crucial glycolytic enzyme that catalyzes the first essential step of glucose metabolism. HK-II is reportedly highly expressed in some human solid carcinomas by many studies. But for laryngeal carcinoma, there is only one. Till now, no studies have directly targeted inhibited HK-II and enhanced the radiosensitivity of laryngeal carcinoma. Accumulating evidence has shown that dysregulated signaling pathways often result in HK-II overexpression. Here, we summarize recent advances in understanding the association among the Warburg effect, HK-II, and the radioresistance of laryngeal carcinoma. We speculate on the feasibility of enhancing radiosensitivity by targeted inhibiting HK-II signaling pathways in laryngeal carcinoma, which may provide a novel anticancer therapy.

The Warburg effect plays an important role in the proliferation and invasion of malignant tumors. Glucose transporter 1 and hexokinase II are two key energy transporters involved in mediating the Warburg effect. This review will analyze the mechanisms of these two markers in their effects on the biological behavior of head and neck cancer.

BackgroundRadiotherapy does not show good efficacy against laryngeal cancer due to radioresistance. Cancer stem cells (CSCs) are considered among the causes of radioresistance. Inhibition of glucose transporter-1 (GLUT-1) using GLUT-1 small interfering RNA (siRNA) may enhance the radiosensitivity of laryngeal cancer cells, but the underlying cellular mechanisms remain unclear.MethodsThe CD133+-Hep-2R cell line was established with repeated irradiation and magnetic-activated cell sorting. The effects of irradiation on CD133+-Hep-2R cells were examined by CCK-8 assay, Transwell assay, quantitative real-time polymerase chain reaction (RT-PCR), and Western blotting. The effects of GLUT-1 siRNA on the radiosensitivity of CD133+-Hep-2/2R cells were examined by RT-PCR, Western blotting, CCK-8 assay, colony formation assay, and Transwell assay in vitro and in a xenograft tumor model in nude mice. The cellular mechanism of enhanced radiosensitivity associated with GLUT-1 siRNA was investigated. The cell cycle and apoptosis rate were analyzed by flow cytometry, and the repair capability was examined by determining the levels of RAD51 and DNA-PKcs.ResultsCD133+-Hep-2/2R cells showed stronger proliferation, lower apoptosis rate, lower percentage of G0/G1 phase cells, higher percentages of S and G2/M phase cells, and higher expression levels of GLUT-1 than Hep-2/2R cells. Transfection with GLUT-1 siRNA inhibited the proliferation and invasive capability of CD133+-Hep-2R cells by inhibiting GLUT-1 expression, which also caused a redistribution of the cell cycle (higher proportion of cells in the G0/G1 phase and lower proportion in the S and G2/M phases), increased the apoptosis rate, and reduced DNA repair capability by suppressing RAD51 and DNA-PKcs expression.ConclusionThe results of this study suggest that GLUT-1 siRNA can enhance the radiosensitivity of CD133+-Hep-2R cells by inducing a redistribution of cell cycle phases, inhibiting DNA repair capability, and increasing apoptosis. Inhibition of GLUT-1 may have therapeutic potential for interventions to increase the radiosensitivity of laryngeal CSCs.

Beclin 1, a positive regulator of autophagy, behaves as a double-edged sword in tumorigenesis. Beclin 1 contributes to tumor suppression by removing defective or damaged organelles and other cellular components; however, its activity can also stimulate cancer initiation and progression. In head and neck cancer, Beclin 1 overexpression promotes autophagy, which limits DNA damage and chromosomal instability and increases necrosis and inflammation by impacting apoptotic and autophagic pathways. This paper reviews the relationship between Beclin 1, carcinogenesis and head and neck cancer prognosis.

Background: Enhanced glucose uptake and autophagy are means by which cells adapt to stressful microenvironments. In this study, we investigated the roles of glucose transporter-1 (GLUT-1) and autophagy in laryngeal carcinoma stem cells under hypoxic and low-glucose conditions. Materials and Methods: CD133-positive Tu212 laryngeal carcinoma stem cells were purified by magnetic-activated cell sorting and subjected to hypoxic and/or low-glucose conditions. Proliferation was evaluated using a cell-counting kit and a clone-formation assay, and migration capability was measured through a Transwell assay. Autophagy was assessed using transmission electron microscopy. Gene silencing was monitored using shRNA technology and autophagy regulation was manipulated using rapamycin, 3-MA, or chloroquine. Gene expression levels were evaluated by quantitative reverse transcriptionpolymerase chain reaction and protein levels were assessed via Western blotting. Results: Compared to CD133-negative cells, CD133-positive cells showed increased proliferation and migration capabilities, and reduced apoptosis, under hypoxic or low-glucose conditions. CD133-positive cells also showed increased expression of GLUT-1 and autophagy activity. Finally, GLUT-1 knockdown or autophagy inhibition reduced the proliferation and migration of CD133-positive laryngeal carcinoma stem cells. Conclusion: Enhanced glucose uptake and autophagy maintain the tumor behaviors of CD133-positive laryngeal carcinoma stem cells under hypoxic and low-glucose conditions.