Date of Award

Summer 2020

Document Type

Open Access Thesis

Department

Biomedical Engineering

First Advisor

Sajish Mathew

Abstract

Breast cancer is one of the most commonly occurring cancers in women. 70% of breast cancer patients express ERα and are treated with tamoxifen (Tam), a drug that is used to directly target ERα. However, 20-30% of cancer patients develop a resistance to Tam. This resistance leads to a worse prognosis and other treatments such as DNA damaging drugs or radiation to eliminate these cells. Resveratrol (RSV) is a polyphenolic- compound found in plants such as grapes and hellebore and is known to evoke anti-cancer effects. While natural resveratrol exists as a mixture of both cis- and trans- isomers, so far, the isomer specific anti-cancer effects of RSV and their mechanisms of action of growth inhibitory effects are not well understood. Most recent studies have demonstrated that eukaryotic tyrosyl-tRNA synthetase (TyrRS)- an essential component of the protein synthesis machinery is a direct target of cis-RSV. While there are no apparent differences in the cellular levels of TyrRS in the WT T47D cells, treatment with cis-RSV resulted in a significant upregulation of TyrRS in the Tam resistant (TamR) T47D cells. Consistent with the inhibitory effect of cis-RSV on the L-tyrosine activation for protein synthesis by TyrRS, treatment with cis-RSV resulted in a greater growth inhibition in TamR T47D cells. Further, cellular signaling pathway analysis demonstrated that treatment with cis-RSV also resulted in a pronounced inhibitory effect on mammalian target of rapamycin complex 1 (mTORC1) signaling that drives protein synthesis in the TamR T47D cells. Therefore, cis-RSV-mediated inhibition of mTOR signaling and TyrRS function in translation would in part be responsible for the growth inhibitory effects of cis-RSV. However, unlike cis-RSV, trans-RSV evoked growth inhibitory effects in both WT and TamR T47D. Although trans-RSV downregulated TyrRS in WT T47D, it did not affect TyrRS levels in TamR T47D. Therefore, utilizing a combination of growth inhibition assays, immunofluorescent imaging and western blot analysis primarily within WT and TamR T47D cells, this study implies that the anti-cancer effect of cis-RSV correlates with the cellular level of TyrRS whereas the anti-cancer effects of trans-RSV is independent of cellular level of TyrRS.

Available for download on Monday, August 15, 2022

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