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

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.

ATF6 prevents DNA damage and cell death in colon cancer cells undergoing ER stress

“…In particular, UPR activation may lead to an impairment of DDR and increase the susceptibility of cancers to the treatments by DNA damaging agents, as reported for example in glioblastoma [ 25 ]. At this regard, we have recently reported that ER stress/UPR activation induced by Zinc chloride triggered a stronger p53 activation and upregulated CHOP in lymphoma cells exposed to low dose radiation, potentiating their-mediated cytotoxic effect [ 10 ].…”

“…However, when the protective functions of UPR are overwhelmed, PERK/eIF2 alpha axis activation can also promote cell death, i.e., by upregulating the pro-apoptotic molecule C/EBP Homologous Protein (CHOP), that alters the balance between the pro-apoptotic and anti-apoptotic Bcl-2 family proteins [ 8 ]. Regarding the impact of PERK/eIF2 alpha axis on DDR, it has been reported that its activation may be involved in the proteasomal degradation of RAD51, increasing DNA damage [ 9 , 10 ]. Finally, few studies have investigated whether ATF6 might influence DDR, while it is known that it mainly sustains cell survival in the course of ER stress, for example by upregulating the ER chaperone Binding immunoglobulin protein (BiP), that promotes protein re-folding and lowers ER stress [ 11 ].…”

Interconnected Adaptive Responses: A Way Out for Cancer Cells to Avoid Cellular Demise

“…This implies that pathological changes occurring in the cytoplasm can be sensed by the nucleus and vice versa. Several studies have explored the interplay between ER stress/UPR and DDR ( Figure 5 ), showing that the induction of ER stress and PERK activation can reduce the capacity of cells to repair DNA damage, inducing the degradation of RAD51 [ 58 , 59 ]. However, PERK has been reported to also sustain DNA repair in other cancer cell types, increasing radio-resistance [ 60 ].…”

“…Interestingly, CHOP may, in turn, sustain the transcription of DUSP5 to mediate the dephosphorylation of ERK1/2 [ 62 ], a kinase able to preserve cancer cell survival either in the course of ER stress and/or genotoxic stress [ 63 , 64 ]. ERK1/2 may indeed counteract the pro-apoptotic function of wtp53 [ 59 , 65 ], another protein that bridges UPR to DDR. Of note, p53 contributes to the transcription of DUSP5 and thus to the inhibition of ERK1/2 [ 66 ] in a negative feedback loop.…”

New Zinc-Based Active Chitosan Films: Physicochemical Characterization, Antioxidant, and Antimicrobial Properties

“…The accumulation of Zn in the human body does not produce toxic effects, while, on the contrary, a lack of this metal ion causes severe injuries on the immune system ( Stefanidou et al, 2006 ). Within the development of new metal-based drugs, wide interest is recently turned to the use of Zn(II) coordination complexes, with low toxicity and low side effects, in medicinal therapeutics and biosensors ( Drewry and Gunning 2011 ; Gonnella et al, 2022 ). Our studies, among others, have been focused on the antitumor activity of Zn(II) complexes containing N,N-chelating ligands and acylpyrazolones, promising systems to verify the metal–ligand synergistic effects ( Liguori et al, 2010 ; Marchetti et al, 2020 ).…”