Unfolded Protein Response manipulation in cancer treatment

Cancer cells are exposed to intrinsic and extrinsic factors that alter the homeostasis of the endoplasmic reticulum (ER), resulting in constitutive ER stress. To adapt to this stress, cancer cells activate the unfolded protein response (UPR), which usually sustains their survival. However, the activation of UPR can be considered a "double-edged sword", as it may also trigger cell death, i.e. in conditions of too long or intense stress. Approaches based on the manipulation of UPR are emerging as promising strategies for the treatment of cancer, either alone or in combination with existing drugs. In this study, we shed more light on the molecular mechanisms underlying the effects of UPR targeting by using natural compounds, such as Resveratrol, Curcumin, and DPE, or drugs that specifically alter ER homeostasis, such as Thapsigargin and Tunicamycin. By pharmacologic and genetic strategies, we observed that the UPR sensors, IRE1α, PERK, and ATF6, have different, and sometimes opposite, roles in balancing death/survival in stressed cells, also depending on the cellular context and the genetic background. For example, while the inhibition of ATF6 was the most effective in decreasing the survival of colon cancer cells undergoing ER stress, the inhibition of IRE1α was the most promising strategy, both in vitro and in vivo, for the treatment of B-cell lymphomas. Furthermore, in agreement with previous studies, we evidenced the close relationship between the UPR and other adaptive responses, such as autophagy and DNA damage response (DDR), influencing the resistance to anti-tumor treatments. In this regard, we described for the first time the role of ATF6 in protecting cells from cell death and DNA damage by sustaining the expression of BRCA1 in TG- or DPE-treated cells. Moreover, we evidenced a new role of ATF6 in supporting lysosomal function, thus directly linking UPR to autophagy. The latter process, together with chaperone mediated autophagy (CMA) were activated by ER stress and contributed to the degradation of mutp53 protein, with important implications for anti-cancer therapy. From these studies, it emerges that UPR and its dynamic interplay with other adaptive responses may be manipulated with important consequences in term of death/survival of stressed cancer cells and that the outcome may be dependent on the cellular context.