Cellular metal sequestration and redox stress by thiosemicarbazones induces endoplasmic reticulum stress in tumors to suppress cancer progression

Endoplasmic reticulum (ER) stress and its response, the UPR, are activated in cancer, inducing oncogenic transformation/progression. An innovative strategy is to induce lethal activation of the UPR using novel thiosemicarbazones (TCs) that form cellular redox active metal complexes. TCs demonstrate potent anti-tumour/-metastatic activity in vivo with a lead agent being assessed in clinical trials in advanced cancer patients (NCT02688101). Hence, studies examined the mechanisms by which TCs alter the UPR in multiple cancer cells to suppress cancer proliferation and migration. Our studies demonstrated that TCs significantly induced high levels of ER stress, increasing the activation of pro-apoptotic UPR signals (i.e., p-eIF2α, ATF4, CHOP), while suppressing UPR survival signals (e.g. XBP1s, p58IPK). In contrast, redox inactive DFO and the ER stress-inducing agent, tunicamycin, had little or no effect on these proteins. Moreover, it was demonstrated that anti-oxidants could inhibit TC-mediated activation of the UPR, while pro-oxidants enhanced activity. Silencing the UPR reduced TC-mediated pro-apoptotic activity and migration inhibition. In conclusion, the induction of lethal ER stress via iron sequestration and the generation of ROS is crucial for the anti-cancer activity of TCs.