Targeting of TOP1mt to Trigger a Novel Pathway for Anti-tumor Drugs (2011)

Undergraduates: Swetha Pasala, Swetha Pasala

Faculty Advisor: Bob Goldstein
Department: Biology

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Chemotherapeutic drugs commonly target an apoptotic pathway triggered by the p53 protein. However, this treatment falls short when certain cancer tissues are found to be resistant to the action of the drugs – one such example being the commonly-used drug, etoposide. In this experiment, we explore the proteins within the p53 pathway of proteins, specifically focusing on the role of enzyme, Mitochondrial Topoisomerase I (TOP1mt), which relieves topological stress during DNA replication, within the pathway. Experimentation was conducted on Mouse Embryonic Fibroblast cells, and the first round of assays tested cell viability confirmed that MEFs that were missing the TOP1mt were more viable under etoposide treatment than MEFs under the etoposide treatment that had TOP1mt. Moreover, assays testing the possible relationship between the activity of TOP1mt and the phosphorylation of the enzyme ataxia telangiectasia mutated (ATM) protein, indicated a strong level of correlation. A membrane potential assay indicated a decrease in cellular membrane potential after etoposide treatment in which indicated an apoptotic tendency of the cell. Thus, the TOP1mt enzyme functions in phosphorylating ATM within the apoptotic pathway induced by etoposide-derived DNA damage. The experimentation also suggests that an increase in the potency of the anti-cancer drug, etoposide, can be seen through an increase in TOP1mt production – possibly through the use of a drug.