IRE1 Alpha/XBP1 Axis Sustains Primary Effusion Lymphoma Cell Survival by Promoting Cytokine Release and STAT3 Activation

Gonnella, Roberta; Montani, Maria Saveria Gilardini; Guttieri, Luisa; Romeo, Maria Anele; Santarelli, Roberta; Cirone, Mara

doi:10.3390/biomedicines9020118

Cited by 20 publications

(20 citation statements)

References 35 publications

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“…The induction of cell death by exacerbating ER stress in cancer cells, which are basally stressed compared to normal cells, or the manipulation of UPR sensor signaling to obtain this effect are emerging as promising anticancer strategies [29]. From previous studies, including those performed in our laboratory, it has emerged that UPR strongly influences processes that are deeply involved in cancerogenesis, such as cytokine release [30,31], EMT, angiogenesis [32,33], and anticancer immune response [7,34]. Oncogenes have been shown to activate UPR, such as in the case of c-myc, which through this mechanism promotes pro-survival autophagy [35], while mutp53 has been reported to sustain ATF6 activation to promote cancer cell survival [26].…”

Section: Discussionmentioning

confidence: 99%

Role of UPR Sensor Activation in Cell Death–Survival Decision of Colon Cancer Cells Stressed by DPE Treatment

et al. 2021

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Polyphenols have been shown to possess several beneficial properties, including properties involved in the prevention or treatment of cancer. Among these polyphenols, a leading role is played by dihydroxyphenylethanol (DPE), the most powerful antioxidant compound contained in the olive oil. DPE has been previously reported to induce endoplasmic reticulum (ER) stress and to reduce cell survival in colon cancer, one of the most common and aggressive cancers in developed countries. In this study, we further investigated the activation of UPR by DPE and explored the roles of the three UPR sensors, inositol-requiring enzyme (IRE) 1 alpha, protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor (ATF6), in the cell death–survival decision of wt and mutp53 colon cancer cells and the underlying mechanisms involved. We also unveiled a new interplay between ATF6 and wt, as well as mutp53, which may have important implications in cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Role of UPR Sensor Activation in Cell Death–Survival Decision of Colon Cancer Cells Stressed by DPE Treatment

et al. 2021

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“…BC3 and BCBL-1 PEL cells, harboring wt and partially functioning p53 [ 24 ], were treated with 25 and 50 μM of Zinc for 24 h and its impact of on ER stress/UPR, basally activated in these lymphoma cells [ 23 ], was evaluated. At this aim, the expression level of BiP and CHOP, which correlates with the pro-survival and pro-death UPR activation, respectively, was investigated.…”

Section: Resultsmentioning

confidence: 99%

“…Cell viability was determined by Trypan Blue (Sigma-Aldrich, St. Louis, MO, USA, R0883) exclusion assay after 24 h of culture, as already described [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

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

Gonnella

Guttieri

Montani

et al. 2022

Biology

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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.

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“…[21] The ER stress sensors, PERK and XBP1, were both reported to promote the survival capacity of cells by activating STAT3. [38,39] PERK was also activated during the process of epithelial-to-mesenchymal transition. [40] M2 and M3 signi cantly upregulated the protein level of PERK and XBP1, whereas M1 signi cantly upregulated XBP1.…”

Section: Discussionmentioning

confidence: 99%

HBV preS mutations promote hepatocarcinogenesis by inducing endoplasmic reticulum stress and up-regulating inflammatory signaling

Cao

Liu²,

Pu³

et al. 2022

Preprint

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We aimed to elucidate the effects and underlying mechanisms of hepatitis B virus (HBV) preS mutations on hepatocarcinogenesis. The association between preS mutations and hepatocellular carcinoma (HCC) occurrence was evaluated using a cohort of 2114 HBV-infected patients. Combo mutations G2950A/G2951A/A2962G/C2964A and C3116T/T31C significantly increased HCC risk in patients without antiviral treatment, whereas preS2 deletion significantly increased the HCC risk in patients who received antiviral treatment. The preS1/preS2/S mutants and their wild-type counterpart were delivered into Sleeping Beauty (SB) mouse models. preS1/preS2/S mutants induced a higher tumor rate and higher serum levels of inflammatory cytokines than did wild type-preS1/preS2/S in SB mice. The preS1/preS2/S mutants induced dramatic alteration of gene expression profiles partially through inducing pro-oncogenic inflammatory cytokine. Through enhancing the retention of HBV S protein in endoplasmic reticulum (ER), the preS1/preS2/S mutants enhanced ER stress, induced the alteration in metabolism, affected the response to hypoxia, and upregulated the protein level of signal transducer and activator of transcription 3 (STAT3). Inhibiting the STAT3 pathway attenuated the positive effects of preS1/preS2/S mutants on cell proliferation. Thus, G2950A/G2951A/A2962G/C2964A, C3116T/T31C, and preS2 deletion promote hepatocarcinogenesis via inducing ER stress, metabolism, and pro-oncogenic STAT3 inflammatory pathways, which can be transformed into specific prophylaxis of HCC.

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IRE1 Alpha/XBP1 Axis Sustains Primary Effusion Lymphoma Cell Survival by Promoting Cytokine Release and STAT3 Activation

Cited by 20 publications

References 35 publications

Role of UPR Sensor Activation in Cell Death–Survival Decision of Colon Cancer Cells Stressed by DPE Treatment

Role of UPR Sensor Activation in Cell Death–Survival Decision of Colon Cancer Cells Stressed by DPE Treatment

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

HBV preS mutations promote hepatocarcinogenesis by inducing endoplasmic reticulum stress and up-regulating inflammatory signaling

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