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Schweinfurthin induces ICD without ER stress and caspase activation.

ABSTRACT: Our previous study showed that one of the schweinfurthin compounds, 5'-methoxyschweinfurthin G (MeSG), not only enhances the anti-tumor effect of anti-PD1 antibody in the B16F10 murine melanoma model, but also provokes durable, protective anti-tumor immunity. Here we further investigated the mechanisms by which MeSG treatment induces immunogenic cell death (ICD). MeSG induced significant cell surface calreticulin (CRT) exposure in a time and concentration dependent manner as well as increased phagocytosis of tumor cells by dendritic cells in vitro. Interestingly, this CRT exposure differs from the canonical pathway in several aspects. MeSG does not cause ER stress and does not require PERK to induce CRT exposure. Caspase inhibitors partially rescue cells from MeSG-induced apoptosis, but fail to reduce CRT exposure. MeSG does not cause ERp57 exposure and the absence of ERp57 expression does not reduce CRT exposure. Finally, an intact ER to Golgi transport system is required for this phenomenon. These results lend support to the development of the schweinfurthin family as drugs to enhance clinical response to immunotherapy and highlight the need for additional research on the mechanisms of ICD induction.

SUBMITTER: Zhang R

PROVIDER: S-EPMC9354771 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Schweinfurthin induces ICD without ER stress and caspase activation.

Zhang Ruoheng R Neighbors J D JD Schell T D TD Hohl R J RJ

Oncoimmunology 20220803 1

Our previous study showed that one of the schweinfurthin compounds, 5'-methoxyschweinfurthin G (MeSG), not only enhances the anti-tumor effect of anti-PD1 antibody in the B16F10 murine melanoma model, but also provokes durable, protective anti-tumor immunity. Here we further investigated the mechanisms by which MeSG treatment induces immunogenic cell death (ICD). MeSG induced significant cell surface calreticulin (CRT) exposure in a time and concentration dependent manner as well as increased ph ...[more]

PMID: 35936984

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Project description:The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. However, the causes and mechanisms of inflammation-mediated liver damage remain poorly understood. Endoplasmic reticulum (ER) stress is an initiator of cell death and inflammatory mechanisms. Although obesity induces ER stress, the interplay between hepatic ER stress, NLRP3 inflammasome activation and hepatocyte death signaling has not yet been explored during the etiology of chronic liver diseases. Steatosis is a common disorder affecting obese patients; moreover, 25% of these patients develop steatohepatitis with an inherent risk for progression to hepatocarcinoma. Increased plasma LPS levels have been detected in the serum of patients with steatohepatitis. We hypothesized that, as a consequence of increased plasma LPS, ER stress could be induced and lead to NLRP3 inflammasome activation and hepatocyte death associated with steatohepatitis progression. In livers from obese mice, administration of LPS or tunicamycin results in IRE1α and PERK activation, leading to the overexpression of CHOP. This, in turn, activates the NLRP3 inflammasome, subsequently initiating hepatocyte pyroptosis (caspase-1, -11, interleukin-1β secretion) and apoptosis (caspase-3, BH3-only proteins). In contrast, the LPS challenge is blocked by the ER stress inhibitor TUDCA, resulting in: CHOP downregulation, reduced caspase-1, caspase-11, caspase-3 activities, lowered interleukin-1β secretion and rescue from cell death. The central role of CHOP in mediating the activation of proinflammatory caspases and cell death was characterized by performing knockdown experiments in primary mouse hepatocytes. Finally, the analysis of human steatohepatitis liver biopsies showed a correlation between the upregulation of inflammasome and ER stress markers, as well as liver injury. We demonstrate here that ER stress leads to hepatic NLRP3 inflammasome pyroptotic death, thus contributing as a novel mechanism of inflammation-mediated liver injury in chronic liver diseases. Inhibition of ER-dependent inflammasome activation and cell death pathways may represent a potential therapeutic approach in chronic liver diseases.

Project description:The VPS37A gene encodes a subunit of the endosomal sorting complex required for transport (ESCRT)-I complex that is frequently lost in a wide variety of human solid cancers. We have previously demonstrated the role of VPS37A in directing the ESCRT membrane scission machinery to seal the phagophore for autophagosome completion. Here, we report that VPS37A-deficient cells exhibit an accumulation of the apoptotic initiator CASP8 (caspase 8) on the phagophore and are primed to undergo rapid apoptosis through the intracellular death-inducing signaling complex (iDISC)-mediated CASP8 activation upon exposure to endoplasmic reticulum (ER) stress. Using CRISPR-Cas9 gene editing and comparative transcriptome analysis, we identified the ATF4-mediated stress response pathway as a crucial mediator to elicit iDISC-mediated apoptosis following the inhibition of autophagosome closure. Notably, ATF4-mediated iDISC activation occurred independently of the death receptor TNFRSF10B/DR5 upregulation but required the pro-apoptotic transcriptional factor DDIT3/CHOP to enhance the mitochondrial amplification pathway for full-activation of CASP8 in VPS37A-deficient cells stimulated with ER stress inducers. Our analysis also revealed the upregulation of NFKB/NF-kB signaling as a potential mechanism responsible for restraining iDISC activation and promoting cell survival upon VPS37A depletion. These findings have important implications for the future development of new strategies to treat human cancers, especially those with VPS37A loss.Abbreviations: ATG: autophagy related; BMS: BMS-345541; CASP: caspase; CHMP: charged multivesicular body protein; DKO: double knockout; Dox: doxycycline; ER: endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; gRNA: guide RNA; GSEA: gene set enrichment analysis; GSK157: GSK2656157; iDISC: intracellular death-inducing signaling complex; IKK: inhibitor of NFKB kinase; IPA: ingenuity pathway analysis; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NFKB/NF-kB: nuclear factor kappa B; OZ: 5Z-7-oxozeaenol; RNA-seq: RNA sequencing; UPR: unfolded protein response; TFT: transcription factor target; THG: thapsigargin; TUN: tunicamycin; VPS: vacuolar protein sorting.

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Schweinfurthin induces ICD without ER stress and caspase activation.

Publications

Schweinfurthin induces ICD without ER stress and caspase activation.

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