Targeting the Unfolded Protein Response for Breast and Pancreatic Cancer Therapy

Cancer cells are continuously challenged by a limited oxygen, nutrients supply, and elevated protein synthesis. All these circumstances induce ER stress and Unfolded Protein Response (UPR). A huge amount of evidence demonstrates that the UPR is a crucial process for cancer cells to keep malignancy but also that, prolonged pharmacological induction of UPR, can be effective for promoting cancer cell death. Here we show that inhibition of the Hexosamine Biosynthetic Pathway (HBP) by means of a specific HBP inhibitor, FR054, causes a prolonged activation of the UPR that induces, in breast cancer (BC) cells, ROS accumulation and cell death. Conversely, such a ROS-dependent mechanism is somewhat inhibited in pancreatic cancer (PC) cells. However parallel inhibition of xCT/SLC7A11, involved in glutathione biosynthesis, by erastin (ERA), a recognized ferroptosis inducer, significantly enhanced the FR054 effect causing a noteworthy increase in cancer cell proliferation arrest and death.