Saturated fatty acids involved in DNA damage response, mediated by IRE1a, to promote chemotolerance

Michigan State University, East Lansing MI

Investigators

Abstract

Saturated free fatty acids (FFA) are prevalent in the American diet. The most common one is palmitate (PA). Elevated levels of FFA in the bloodstream hare linked to several diseases. These include type 2 diabetes, metabolic syndrome, non-alcoholic fatty liver disease, neurodegenerative diseases, heart disease, and cancer. The overall goal of this project is to gain a clearer understanding of the molecular mechanisms by which PA contributes to cancer cell survival. The insights gained should inform the development of new cancer therapeutics. Undergraduate students will be engaged in the research. Students from underrepresented groups will be actively recruited. The role of saturated fatty acids in activating endoplasmic reticulum (ER) stress sensor proteins and altering DNA damage repair will be investigated. Specifically, the focus will be on how saturated fatty acids are involved in the dimerization and activation of inositol-requiring enzyme 1 (IRE1)α. Activation of IRE1α reduces the effectiveness of chemotherapy drugs in killing cancer cells. Fatty acids, such as PA, contribute to changes in the membrane lipid composition, alter the membrane structure and fluidity, affect protein conformation and insertion into the lipid bilayer, and impact cell signaling and function. Recently, the PIs have shown that PA can induce DNA damage repair and that blocking PA activation of IRE1α sensitizes cancer cells to chemotherapy drugs. Here, they will use cancer cell lines expressing wild-type (WT) and mutant IRE1α protein to study the DNA damage repair pathways induced by PA and the role IRE1α plays in this process. The scientific and engineering contribution of this project is the investigation of the biophysical and cellular interactions between PA and IRE1α to gain a clearer understanding of the molecular mechanism by which PA contributes to cancer cell survival. These results could aid the design of novel pharmaceutical agents to treat cancer. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.