(175d) Connecting the Unfolded Protein Response and DNA Damage Response: The Role of IRE1 in DNA Damage Repair Pathways Under Elevated Levels of Palmitate.

Obesity can exacerbate tumor microenvironment and lead to cellular dysfunction. Obesity is known to be a risk factor for cancer progression and is linked to reduced effectiveness of chemotherapy. With the increasing prevalence of obesity in the US population, we need to better understand 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 agreement with this, we found that PA reduced DNA damage in breast cancer MDA-MB-231 cells and brain cancer T98G cells treated with a chemotherapeutic agent, etoposide (a potent inducer for DNA double stranded breaks) and temozolomide (alkylating agent for treating brain tumors), respectively. Furthermore, the cellular protection was mediated by IRE1α function. 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/temozolomide-induced DNA damage. Furthermore, we found that IRE1α plays an important role in regulating H2A.X (a histone involved in DNA damage response) as well as MGMT (main repair protein for resistance towards alkylating agent).

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, and (ii) a clear understanding of the molecular mechanism by which PA contributes to cancer cell survival will aid the development of novel therapeutics for treating chemotolerance.