Zinc Supplementation Enhances the Pro-Death Function of UPR in Lymphoma Cells Exposed to Radiation

SIMPLE SUMMARY: It is of fundamental importance to find strategies able to reduce the minimum doses of anticancer treatments, such as radiations, and concomitantly maintain efficient killing of cancer cells. The interconnection between ER stress and DNA repair may represent a promising approach to obtaining this goal. Here we found that pretreatment of lymphoma cells with Zinc chloride rendered these cells more sensitive to 2 Gy radiation. The exacerbation of ER stress and the activation pro-death function of UPR were among the underlying mechanisms leading to higher cytotoxicity of Zinc/radiation combination treatment. This evidence encourages the use of Zinc to reduce the doses of radiation in the treatment of lymphoma cells, allowing a high cytotoxicity to be obtained while minimizing the side effects. ABSTRACT: We have previously shown that Zinc supplementation triggered ER stress/UPR in cancer cells undergoing treatment by genotoxic agents, reactivated wtp53 in cancer cells harboring mutant p53 (mutp53) and potentiated the activity of wtp53 in those carrying wtp53. In this study, we used Zinc chloride alone or in combination with 2 Gy radiation to treat Primary Effusion Lymphoma (PEL) cells, an aggressive B-cell lymphoma associated with KSHV that harbors wt or partially functioning p53. We found that Zinc triggered a mild ER stress/UPR in these lymphoma cells and activated ERK1/2, molecule known to sustain cell survival in the course of UPR activation. In combination with radiations, Zinc triggered a stronger p53 activation that counteracted its mediated ERK1/2 phosphorylation, further upregulating the UPR molecule CHOP and promoting cell death. These data suggest that Zinc supplementation could be a promising strategy to reduce the doses of radiation and possibly of other DNA-damaging agents to obtain an efficient capacity to induce lymphoma cell death.