Targeting cellular metabolism to reduce head and neck cancer growth

Jian Yang,Bidisha Paul,Wonkyu Seo,Wenbo Yan,Yaoyu Wang,Xin Li,Yuqi Guo,Cuijie Lu,Liang Luo,Ruohan Zhang,Deepak Saxena

doi:10.1038/s41598-019-41523-4

Abstract

Head and neck squamous cell carcinoma (HNSCC) presents a major public health concern because of delayed diagnosis and poor prognosis. Malignant cells often reprogram their metabolism in order to promote their survival and proliferation. Aberrant glutaminase 1 (GLS1) expression enables malignant cells to undergo increased glutaminolysis and utilization of glutamine as an alternative nutrient. In this study, we found a significantly elevated GLS1 expression in HNSCC, and patients with high expression levels of GLS1 experienced shorter disease-free periods after therapy. We hypothesized that the GLS1 selective inhibitor, bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), which curtails cells’ glutamine consumption, may inhibit HNSCC cell growth. Our results support the idea that BPTES inhibits HNSCC growth by inducing apoptosis and cell cycle arrest. Considering that metformin can reduce glucose consumption, we speculated that metformin would enhance the anti-neoplasia effect of BPTES by suppressing malignant cells’ glucose utilization. The combination of both compounds exhibited an additive inhibitory effect on cancer cell survival and proliferation. All of our data suggest that GLS1 is a promising therapeutic target for HNSCC treatment. Combining BPTES with metformin might achieve improved anti-cancer effects in HNSSC, which sheds light on using novel therapeutic strategies by dually targeting cellular metabolism.

Highlights

Head and neck cancer is the sixth most common cancer worldwide, accounting for around 2.5% of new cancer cases and 1.9% of deaths annually[1]
We showed that the combined application of BPTES and metformin, which hindered glutamine and glucose consumption, achieved additive suppression of Head and neck squamous cell carcinoma (HNSCC) growth
Glucose-independent glutamine metabolism via the tricarboxylic acid (TCA) cycle has been shown to be essential for malignant cell proliferation and survival within hypoxic and nutrient-depleted tumor microenvironments[23]; this process further highlights the initial finding in which targeting glutaminase could be an effective approach for cancer therapy

Summary

Introduction

Head and neck cancer is the sixth most common cancer worldwide, accounting for around 2.5% of new cancer cases and 1.9% of deaths annually[1]. Metformin is used to combat polycystic ovarian syndrome, metabolic syndrome, and obesity[11,12] Since it was approved by the Food and Drug Administration in 1994, metformin has been extensively researched for its anti-neoplastic effects. Our previous study revealed that metformin can regulate the cell cycle and apoptosis by suppressing prostate cancer growth via regulation of oncogene c-Myc[18] and tumor suppressor miRNA-70819. These results indicate that metformin is capable of dampening multiple oncogenic signals that will cause tumor growth suppression. We hypothesized that BPTES and metformin may produce a promising additive effect by concurrently targeting both glutamine and glucose metabolic pathways. We further investigated the BPTES and metformin combination’s anti-tumorigenic potential and their combined effects on apoptosis and cell-cycle arrest in HNSCC cell lines

Methods

Results

Conclusion