Browsing School of Dentistry by Subject "oral squamous cell carcinoma"
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Elucidating the Role of Fatty Acid Synthase in Oral Carcinogenesis and Potential TherapeuticsThe 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.
Role of Survivin and Hexokinase II in the regulation of Autophagy and Apoptosis in Oral Squamous Cell CarcinomaSurvivin, an inhibitor of apoptosis and hexokinase II, a key enzyme in glycolysis are under-expressed in normal oral tissue; while they are over-expressed in oral squamous cell carcinoma (OSCC). Previous studies in our lab have shown a direct correlation between survivin and hexokinase II, using bromo-pyruvic acid, a known hexokinase II inhibitor. Additionally, it has also been shown that there is an increase in the expression of these two biomarkers with the increase in severity of premalignant lesions. These data were obtained from our patient database at Oral Pathology Consultants (OPC) which was compared to the Maryland Cancer Registry (MCR) for a cancer match. Based on this previous work, we decided to study two of the cancer hallmarks in OSCCs; dysregulation of apoptosis and altered cellular metabolism, and molecules associated with them; survivin and hexokinase II. Interestingly, survivin was found to be over-expressed in 80% of OSCCs. Hence, our hypothesis was that in cells during survivin over-expression, treatments with DNA damaging agents will lead to induction of autophagy in OSCCs. To prove this hypothesis, two well known DNA damaging drugs, cisplatin and paclitaxel were used. The basic aim of the study was to down-regulate survivin and study the effect of this down-regulation on autophagy proteins, beclin-1 and mammalian light chain protein kinase, LC3 (autophagy marker). Using a premalignant cell line (Leuk-1) and malignant cell lines (SCC 9 and SCC 25), we have shown down-regulation of survivin using cisplatin and paclitaxel. Survivin is known to inhibit caspases, hence its down-regulate is likely to activate the process of apoptosis. Our western blot results represent down-regulation of beclin-1 as well as the active form of LC3, LC3-II. However, beclin-1 forms a complex with anti-apoptotic proteins, Bcl-2/xL and its down-regulation with chemotherapeutic drugs disturbs the complex, increasing the loss of mitochondrial membrane integrity and ultimately apoptosis. Also, LC3 is a high turn-over protein which can be incorrectly reflected on a western blot. However, further validation of the processes activated due to beclin-1 and LC3 down-regulation will raises a strong possibility of cross-talk between autophagy and apoptosis. Further, literature studies have shown that activation of one signaling pathway regulates key players at transcription and translational levels, which in turn activate or down-regulate other signaling pathways. Our findings support the novel role of the survivin/hexokinase II axis in the regulation of autophagy and apoptosis, in both dysplastic oral lesions and in OSCC.