Induction of Paraptosis: A novel strategy to overcome radiation resistance in cancer cells

2020 Fiscal Year Annual Research Report

• Project/Area Number: 18K15585
• Research Institution: University of Toyama
• Principal Investigator: REHMAN MATIUR 富山大学, 学術研究部医学系, 特命助教 (10810921)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: Paraptosis / Radiation / Oxidative stress

Outline of Annual Research Achievements

The study was aimed to develop a cancer cell death enhancement method by utilizing drugs/chemical modifiers of intracellular redox signaling that induces distinct cancer cell death to improve therapy resistance. Results achieved from this study strongly manifests that bardoxolone methyl (CDDO-Me or RTA 402) induced paraptosis particularly in HCT-116 colorectal cancer cells. However, in other colorectal cancer cells such as HCT-115, DLD-1 and Colo 205 paraptosis was not observed. CDDO-Me mediated oxidative stress, release of calcium and ER-stress are key factor for the induction of paraptosis. CHOP was found as the key modulator of ER-stress mediated paraptosis in HCT-116 cells. To determine the rational for CDDO-Me induced paraptosis in HCT-116 cells gene chip analysis was performed at different time points. Gene chip data showed that several genes were up regulated and down regulated only in the CDDO-Me treatment than that of untreated control. Following gene chip analysis all the results will be published as a research paper in the future.
In addition, it was also found that the FDA-approved drug romidepsin (FK228) enhanced hyperthermia-induced cancer cell death. Interestingly, FK228 increased the sensitization of those cancer cells, which are considered resistant to hyperthermia cancer therapy. This is the one method to improve overall cancer therapy resistance. The results obtained will be published as a research paper.