470668 Palmitate Induces the Loss of Desmosomes through Endoplasmic Reticulum (ER)-Stress to Promote Cancer Progression
One of the first steps of EMT is the disassembly of epithelial cell-cell contacts (e.g. adherens junction, desmosomes, etc.), and the loss of cell polarity. Previously, through an integrative analysis (computational and experimental), we identified that the desmoplakin (DSP) protein is perturbed by PA[Wang et al, 2011]. The DSP protein is an obligate component of functional desmosomes; intercellular junctions responsible for cell-cell adhesion. DSP together with plakoglobin and plakophilin forms the intracellular desmosomal plaque, which also serves as an anchor for keratin intermediate filament attachment. Reduced DSP protein expression can lead to loss of cell-cell adhesion through desmosomes, disruption of the keratin intermediate filament network, and has been observed in liver carcinoma and in cell lines established from metastatic patient tumor samples. A reduction in desmosomes has been observed in cells undergoing EMT, whereas during the reversal of mesenchymal to epithelial transition desmosomes were restored.
While loss of desmosomes and DSP has been reported in HCC [Wang et al, 2011], the role of FFAs in modulating DSP expression and the role of DSP in EMT and metastasis is unknown. Our research focuses on uncovering the mechanism by which elevated saturated fatty acids induce the loss of cell adhesion and enhance migration, mediated through IRE1α protein and ER stress. In contrast to prior studies which do not explain how PA induces ER-stress and the unfolded protein response (UPR) signaling pathways, we pursued a novel line of investigation, and assessed whether PA interacts directly with the kinase proteins in the UPR (specifically IRE1α) to activate ER stress and its downstream signaling to induce EMT mediated by the loss of DSP.
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