Unraveling the Molecular Nexus between GPCRs, ERS, and EMT

Figure 3

GPCR-ERS-UPR in cancer. Overexpression of the GPCRs with oncogenic roles (e.g., CXCR4 and LPAR, green) in the conditions of hypoxia, nutrient deprivation, ROS, activated oncogenes, or acidic environment is associated with activation of survival pathways (PI3K/AKT/NF-κB, MAPK, and growth factor mediated signaling) to support cancer cell survival. At the same time, via regulation of IRE, ATF6, and PERK, GPCRs can inhibit cell death pathways, apoptosis, and cytotoxic autophagy (signaling indicated with green arrows). On the other hand, GPCRs with anticancer roles (MT1RA/B and CNR1/2, red) are associated with activation of the ERS-mediated UPR signaling to induce apoptosis and autophagy-related cell killing (signaling indicated with red arrows). Complex bidirectional crosstalk between UPR pathways and various cell survival and growth signaling pathways is involved in mediating the GPCR-related cancer cell fate. However, the exact sequence of this crosstalk for a given GPCR or other possible mediators still needs to be explored.