Elucidating the Role of Fatty Acid Synthase in Oral Carcinogenesis and Potential Therapeutics

Abstract

The 5-year overall survival rate in oral squamous cell carcinoma (OSCC) has remained relatively unchanged over decades, due to late stage diagnosis and high recurrence rates. This work investigates two potential contributing risk factors associated with OSCC development: nicotine, present in traditional combustible tobacco cigarettes and electronic nicotine delivery systems, and high glucose as associated with Type II diabetes and hyperglycemia. A novel therapeutic, TVB-3166, for OSCC treatment was also studied through in vitro experiments, which may help improve clinical treatments for fully developed, often late-stage OSCC. Through cell viability and growth assays, scratch assays to mimic in vitro migration, and western blotting, we determined that both nicotine and high glucose caused oral dysplastic keratinocytes to exhibit an increase in malignant-like behavior. High expression levels of fatty acid synthase (FASN), a key de novo lipogenic enzyme, have been implicated in OSCC, and this work presents the first evidence that both nicotine and high glucose markedly increase oral dysplastic keratinocyte FASN expression, which drives epidermal growth factor receptor (EGFR) signaling, a key pro-oncogenic signaling pathway commonly associated with oral carcinogenesis. We also demonstrate that TVB-3166, a novel selective FASN inhibitor, induces apoptosis and reduces in vitro OSCC cell migration. Moreover, TVB-3166 inhibits basal EGFR activity and several other oncogenic signaling proteins. This further establishes a potential role for FASN and EGFR not only in the progression of oral epithelial dysplastic pre-malignant lesions, but in fully-developed OSCC tumors. Overall, this work suggests that both nicotine and high glucose play a role in OSCC progression, specifically as it relates to FASN-dependent EGFR activation. Further, the novel drug TVB-3166 should be investigated in future pre-clinical animal models as a potential adjunct to OSCC therapeutics. Through an improved understanding of risk factors for OSCC development, as well as determination of novel therapeutic strategies, this work aims to improve overall patient survival through prevention of OSCC development, as well as discovery of new adjunctive treatments for fully established tumors.