Recent research in cancer have found that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are highly induced in various tumors and are closely associated with cancer cell survival and resistance to anti-cancer treatments. Concomitantly, epidemiological evidences have linked elevated levels of free fatty acids (FFAs) with hepatocellular carcinoma (HCC) tumorigenesis and increased mortality. Of particular interest are saturated long chain-FFAs, notably palmitic acid, which have been implicated in ER stress and numerous diseases, including cancer. We and others have found that palmitic acid activates the IRE1α (inositol-requiring enzyme 1 α) pathway in liver and pancreatic beta-cells. However, the molecular mechanisms of how palmitic acid induces ER stress have not been well established. Through molecular dynamic simulations, mutation studies, and FRET analysis, we uncover that palmitic acid interacts with the cytosolic and transmembrane domains of the IRE1 protein to impact phosphorylation and dimerization of the IRE1 protein and their downstream signaling.
Additionally we found that elevated palmitic acid induces liver cells to undergo epithelial to mesenchymal (EMT), a prerequisite step for cells undergoing metastasis. Analyzing The Cancer Genome Atlas (TCGA) liver cancer dataset, we found the induction of the EMT program is closely associated with the expression of the fatty acid uptake protein CD36, which we confirmed in human HCC tumor samples. Treatment of human liver cancer cells with palmitic acid exacerbated the EMT phenotype, whereas chemical inhibition of CD36 mitigated these effects. Given these results and the literature information linking IRE1α signaling to EMT, we investigated how induction of ER stress by palmitic acid through direct interaction with IRE1α leads to the activation its enzymatic activities and the promotion of EMT.
See more of this Group/Topical: Food, Pharmaceutical & Bioengineering Division