(72g) Activation of IRE1? By Palmitate Leads to Loss of Desmoplakin in Liver and Breast Cancer Cells

Saturated free fatty acids such as palmitate (PA) induce the unfolded protein response (UPR) through the activation of the Inositol Requiring Protein-1 (IRE1). The UPR is designed to mitigate endoplasmic reticulum stress through the activation of downstream effector pathways. Activation of IRE1 leads to splicing of the X-box binding protein (XBP1) mRNA which then is translated into a transcription factor. XBP1 is responsible for activation of genes in the UPR.

Previous studies from our research group have shown that hepatocellular carcinoma progression via the induction of epithelial-to-mesenchymal transition (EMT) is closely associated with high levels of saturated fatty acids. This is characterized by the loss of desmoplakin, a cell adhesion protein leading to increased migration in cancer cell lines. Our research focuses on uncovering the mechanism by which elevated saturated fatty acids induce the loss of cell-cell contact and enhance migration, mediated through the IRE1α-XBP1 axis.

To investigate this, we developed IRE1^-/^- knockout cell lines for liver and breast cancer and analyzed the effect of loss of IRE1 on migration and development of EMT. Our studies indicate that ZEB1, a transcription factor involved in development of EMT, is involved in the regulation of DSP expression. Additionally, the ZEB1 levels are dependent on IRE1 activation by PA.

We also investigated the effect of activation of IRE1 by PA on changes in metabolic genes associated with glycolysis, gluconeogenesis, and fatty acid metabolism. Concurrently, we found that activation of IRE1-XBP1 leads to increased chemo-tolerance in liver cancer cells. Studying the effect of fatty acids on the metabolism, invasiveness and metastatic ability of cells through ER stress sensors like IRE1α provides insights into the biochemical changes induced by fatty acids that contribute to cancer progression and aggressiveness.