A Study in the Effect of Mitochondrial DNA Deletion and Gelsolin Expression in Cancer Drug Resistance

Abstract

Oral squamous cell carcinoma is one of the top ten malignancies in the world According to some reports in Taiwan oral cancer is ranked seventh leading cause of cancer death To cure cancer cisplatin (CDDP) is one of the most potent anti-cancer agents in clinical use for a wide variety of solid tumors However chemoresistance is a problem that lowers the therapeutic efficiency and leads to treatment failure In previous studies the results indicated that gelsolin (GSN) expression levels were positively associated with chemoresistance in vitro and in vivo In chemoresistant cells GSN was highly expressed and CDDP had no significant effect on inducing apoptosis Mitochondrial DNA (mtDNA) defect is known to confer accumulation of intracellular reactive oxygen species (ROS) that contributes the transformation of normal cells to malignant state Recent study also showed the association between mitochondria mutation and chemoresistant phenotype Resveratrol (RES) and tetrahydroxystilbene glucoside (THSG) are herbal extract of similar chemical structure known for prominent antioxidant activity As oxidative stress has been demonstrated to contribute carcinogenesis and tumor progression RES and THSG have been investigated for their roles in cancer prevention and adjuvant therapy In this study we hypothesize the level of mtDNA 4977-bp deletion would affect chemosensitivity of tumor cells and RES or THSG may play certain role in this regard Our results showed that 4977-bp deletion was higher in chemoresistant cancer cell (HONE1-CIS6) than their paired chemosensitive line (HONE-1) The total copy number of mtDNA was lower in HONE1-CIS6 than HONE-1 RES treatment significantly increase mtDNA copy number in both cancer cell lines while no significant effect was observed in 4997-bp deletion The cell viability in two cell lines of RES co-treatment with CDDP was found that there had a great cytotoxic effect to induce apoptosis and enhance the level of apoptotic-related proteins In the future we want to dig deeper into the mechanisms of cytotoxic operation and predict the pathway more clearly to confirm our hypothesis

Date of Award	2016 Sept 2
Original language	English
Supervisor	Dar-Bin Shieh (Supervisor)