Electronic Theses and Dissertations for Graduate School
Add My Work
Author Last Name
TRPM2 Inhibition Increases Oxidative Stress and Reduces Tumor Growth in Neuroblastoma through Modulation of GSH
Restricted (Penn State Only)
Lee, John P
Master of Science
Date of Defense:
March 22, 2017
Barbara Miller, Thesis Advisor
Patricia McLaughlin, Committee Member
Loren Evey, Committee Member
The transient receptor potential melastatin 2 (TRPM2) ion channel modulates cell signaling pathways in response to oxidative stress and is highly expressed in neuroblastoma and other cancers. Previous in vitro experiments generated from neuroblastoma cells in which TRPM2 was depleted with CRISPR/Cas9 technology have demonstrated increased levels of reactive oxygen species (ROS) and an increase in sensitivity to doxorubicin. Xenograft experiments with these cell lines have exhibited an increased sensitivity to doxorubicin and inhibition of tumor growth. Here, the NF-E2 related factor 2 (Nrf2) signaling cascade, which regulates expression of proteins involved in the antioxidant response, was suppressed by TRPM2 depletion. Upstream inhibitors of Nrf2 activity showed increased expression in TRPM2 depleted cells. TRPM2 depleted SH-SH5Y neuroblastoma cells also demonstrated reduced glutathione (GSH) concentrations after doxorubicin treatment. These findings demonstrate the importance of TRPM2 in modulating cell signaling pathways involved in antioxidant production in response to increased ROS. Thus, TRPM2 is a potential target for inhibition as a therapy to reduce tumor growth and increase susceptibility to chemotherapeutic agents through modulation of ROS.
Login using your Penn State access account to view the paper.