Metformin and the Tumor Microenvironment in Oral Squamous Cell Carcinoma

Objectives: Oral Squamous Cell Carcinoma (OSCC) is the sixth most common cancer worldwide, yet 5-year-survival of patients affected with HPV+/- OSCC has not significantly increased during the past several years. Metformin, a known AMPK inhibitor, has been shown to decrease proliferation in several cell lines when administered at supratherapeutic concentrations. Current research suggests controlling stromal activation within OSCC may halt the production of key enzymes such as matrix metalloproteinases (MMPs) and other serine proteases which are known to contribute to invasion and metastasis. Other major enzymes identified by current research as contributing to metastatic pathways are AMPK and ERK1/2. We propose that at therapeutic doses, Metformin may limit the metastatic processes of OSCC, affecting the expression of MMP -1, -2, -3, -9, and -13.
Methods: HPV-/- oral squamous cell carcinoma cells (Cal-27) and HPV 16+ oral squamous cell carcinoma cells (UM-SCC-104) were incubated with varying concentrations of Metformin (1uM - 20mM) for 24 hours to determine the effect of Metformin on the expression of MMPs. Protein samples were collected and blotted for HtrA-1, MMP -1, -2, -3, -9, -13, ERK1/2, and AMPK.
Results: Higher metformin doses resulted in decreased viability of the cell line. At therapeutic concentrations, MMP-2 and -9 expression was decreased. This effect seems to be mediated by AMPK and ERK1/2.
Conclusions: Metformin may present as a promising therapeutic agent for reducing the expression of MMPs known to propagate cellular invasiveness of the HPV+/- oral squamous cell carcinoma lines: Cal-27 and UM-SCC-104. With increasing rates of infection with high-risk strains of HPV and increasing incidences of oral and oropharyngeal squamous cell carcinoma, targeting and controlling the expression of molecules involved in tumor metastasis may present therapeutic adjuncts for these patients in the future.