Targeting the Glucose-Insulin Link in Head and Neck Squamous Cell Carcinoma Induces Cytotoxic Oxidative Stress and Inhibits Cancer Growth

Simbarashe Mazambani, Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas.
Seong-Ho Park, Department of Oncology Science, The University of Oklahoma College of Medicine, Stephenson Cancer Center, Oklahoma City, Oklahoma.
Joshua H. Choe, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts.
An H. Nguyen, Department of Oncology Science, The University of Oklahoma College of Medicine, Stephenson Cancer Center, Oklahoma City, Oklahoma.
Bok-Soon Lee, Department of Otolaryngology, Ajou University School of Medicine, Suwon, Korea.
Ji Yun Jeong, Department of Pathology, Kyungpook National University School of Medicine, Daegu, Korea.
Shin Yup Lee, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
Chul-Ho Kim, Department of Otolaryngology, Ajou University School of Medicine, Suwon, Korea.
Yea-In Park, Department of Biochemistry & Molecular Medicine, George Washington University School of Medicine and Health Sciences, GW Cancer Center, Washington, District of Columbia.
Joselyn Padilla, Department of Biochemistry & Molecular Medicine, George Washington University School of Medicine and Health Sciences, GW Cancer Center, Washington, District of Columbia.
Jiyoung Lee, Department of Biochemistry & Molecular Medicine, George Washington University School of Medicine and Health Sciences, GW Cancer Center, Washington, District of Columbia.
Dinesh Thotala, Department of Radiation Oncology, The University of Oklahoma College of Medicine, Stephenson Cancer Center, Oklahoma City, Oklahoma.
Tae Gyu Oh, Department of Oncology Science, The University of Oklahoma College of Medicine, Stephenson Cancer Center, Oklahoma City, Oklahoma.
Pankaj K. Singh, Department of Oncology Science, The University of Oklahoma College of Medicine, Stephenson Cancer Center, Oklahoma City, Oklahoma.
Hoon Hur, Department of Surgery, Ajou University School of Medicine and Cancer Biology Graduate Program, Ajou University Graduate School of Medicine, Suwon, Korea.
Junho K. Hur, Department of Genetics, College of Medicine, Hanyang University, Seoul, Korea.
Jung-Whan Kim, Department of Oncology Science, The University of Oklahoma College of Medicine, Stephenson Cancer Center, Oklahoma City, Oklahoma.
Tae Hoon Kim, Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas.

Document Type

Journal Article

Publication Date

6-1-2025

Journal

Cancer research communications

Volume

5

Issue

6

DOI

10.1158/2767-9764.CRC-23-0506

Abstract

UNLABELLED: Head and neck squamous cell carcinoma (HNSCC) remains a clinically challenging malignancy with limited targeted therapy options and poor patient outcomes. Thus, identifying unique dependencies, including HNSCC-specific metabolic reprogramming, is imperative for improving treatment strategies for this disease. In this study, we show that HNSCC relies on elevated glucose transporter 1 (GLUT1)-mediated glucose uptake to support redox homeostasis and tumor growth. Analyses of GLUT1 expression data in tumors and cancer cell lines reveal significant upregulation of GLUT1 in HNSCC relative to both normal tissue and other cancer subtypes and that high GLUT1 expression correlates with poorer clinical outcomes. Using a basal epithelial layer-specific GLUT1-knockout mouse model, we demonstrate that GLUT1 ablation in HNSCC cells of origin markedly attenuates tumor initiation and progression, implicating the necessity of GLUT1 in HNSCC tumorigenesis. Building on this observation, combining pharmacologic inhibition of GLUT1 with pro-oxidants such as vitamin C and auranofin induces potent cytotoxicity in vitro and in vivo, partly by precipitating oxidative stress. We further observe that insulin signaling is required to sustain glucose uptake and redox homeostasis, as insulin receptor knockdown decreases proliferation and increases reactive oxygen species levels. Together, these results suggest that although GLUT1 overexpression is a key driver of glucose uptake, insulin signaling also contributes to the metabolic and oncogenic pathways underlying HNSCC progression. Consequently, strategies that co-target GLUT1 and insulin signaling to restrict glucose flux may synergize with pro-oxidant therapies, offering a promising therapeutic avenue for HNSCC. SIGNIFICANCE: Enhanced GLUT1 expression and oncogenic insulin signaling drive elevated glucose uptake in HNSCC, which contribute to the maintenance of redox homeostasis and tumor growth. Disrupting both glucose uptake and redox balance may offer a promising therapeutic approach.

Department

Biochemistry and Molecular Medicine

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