(574c) IRE1a Regulates MGMT to Modulate DNA Damage Under Elevated Level of Palmitate

Obesity is a known risk factor for cancer progression and is linked to reduced effectiveness of chemotherapy. With the increasing prevalence of obesity in the US population, a better understanding is needed on how obesity affects chemotherapy. Previously we showed that palmitate (PA), the most common saturated fatty acid in the human body is elevated in obese patients and induces endoplasmic reticulum (ER) stress by promoting the dimerization of inositol-requiring enzyme 1α (IRE1α). More recently, we found that PA promotes cancer progression and metastasis, mediated by IRE1α.

Increasing evidence supports cross-talk between protein homeostasis (ER stress response) and genome integrity (DNA damage response). In support, we found that PA reduced DNA damage in breast cancer MDA-MB-231 cells treated with a chemotherapeutic agent (etoposide - a potent inducer for DNA double stranded breaks), mediated by IRE1α. We employed both wild-type and IRE1α knockout cells and demonstrated that PA activation of IRE1α contributed to increasing DNA damage repair activity in response to etoposide-induced DNA damage. Additionally, we found that IRE1α plays an important role in regulating O6-methylguanine-DNA-methyltransferase (MGMT), which is beyond its conventional role of repairing DNA damage caused by methylating agents.

This research is the first to show that PA contributes to DNA damage repair mediated through IRE1α, enhancing the survival of cancer cells treated with anti-cancer drugs. This is significant because (i) PA and ER stress are involved in numerous aging diseases, (ii) a clear understanding of the molecular mechanism by which PA contributes to cancer cell survival will aid in the development of novel therapeutics for treating chemotolerance, and (iii) it established a novel role of MGMT in DNA double-strand break repair mediated by PA activation of IRE1α.