Dihydroartemisinin mediating PKM2-caspase-8/3-GSDME axis for pyroptosis in esophageal squamous cell carcinoma.
TL;DR: In this paper, the exact mechanism by which DHA induces pyroptosis to inhibit esophageal squamous cell carcinoma (ESCC) remains unclear, but DHA treatment was applied to ESCC cells and some dying cells exhibited the characteristic morphology of pyroPTosis, such as blowing large bubbles from the cell membrane, accompanied by downregulation of pyruvate kinase isoform M2 (PKM2), activation of caspase-8/3, and production of GSDME-NT.
About: This article is published in Chemico-Biological Interactions.The article was published on 2021-12-01. It has received 15 citations till now. The article focuses on the topics: Pyroptosis & Caspase 8.
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TL;DR: The molecular mechanisms by which phytochemicals prevent the development of cancer are reviewed and it is highlighted that the mechanisms and promising applications are required to be understood to decisively establish the anti-cancer efficacy of natural phytochemistryicals.
Abstract: Increasing evidence has been reported regarding phytochemicals, plant secondary metabolites, having therapeutic functions against numerous human diseases. Recently, phytochemicals (flavonoids, polyphenols, terpenoids, alkaloids, saponins, coumarins and so on) have shown promising anti-cancer efficacy with their distinct advantages of high efficiency and low toxicity. They regulate programmed cell death (apoptosis, pyroptosis, and autophagy), migration and senescence-related signaling pathways of cancer via the modulation of reactive oxygen species (ROS), mitogen activated protein kinase (MAPK) pathway, deleted in liver cancer 1 (DLC1), nuclear factor κ light-chain-enhancer of activated B cell (NF-κB) pathways and glycolytic enzymes. Here, we review the molecular mechanisms by which phytochemicals prevent the development of cancer. Furthermore, phytochemicals combined with chemotherapeutic agents could target the crosstalk among multiple signal cascades to block chemoresistance and attenuate carcinogenic properties, and can be considered as a novel and potential therapeutic strategy. Our review highlights that the mechanisms and promising applications are required to be understood to decisively establish the anti-cancer efficacy of natural phytochemicals.
10 citations
TL;DR: It is concluded that reactivating GSDME expression and thereby inducing cancer cell-specific pyroptosis could be a potential therapeutic strategy against GC.
Abstract: Gasdermin E (GSDME) is one of the executors of pyroptosis, a type of programmed lytic cell death, which can be triggered by caspase-3 activation upon stimulation. Silenced GSDME expression due to promoter hypermethylation is associated with gastric cancer (GC), which is confirmed in the present study by bioinformatics analysis and methylation-specific PCR (MSP) test of GC cell lines and clinical samples. GC cell lines and mouse xenograft models were used to investigate the pyroptosis-inducing effect of the common cholesterol-depleting, drug simvastatin (SIM), allied with upregulating GSDME expression by doxycycline (DOX)- inducible Tet-on system or DNA methyltransferase inhibitor 5-Aza-2′-deoxycytidine (5-Aza-CdR). Cell viability assessment and xenograft tumour growth demonstrated that the tumour inhibition effects of SIM can be enhanced by elevated GSDME expression. Morphological examinations and assays measuring lactate dehydrogenase (LDH) release and caspase-3/GSDME protein cleavage underlined the stimulation of pyroptosis as an important mechanism. Using short hairpin RNA (shRNA) knockdown of caspase-3 or GSDME, and caspase-3-specific inhibitors, we provided evidence of the requirement of caspase-3/GSDME in the pyroptosis process triggered by SIM. We conclude that reactivating GSDME expression and thereby inducing cancer cell-specific pyroptosis could be a potential therapeutic strategy against GC.
10 citations
TL;DR: PDLs were closely implicated in the biological process and prognosis of GC, and the PLPPS model could serve as a promising tool to advance prognostic management and personalized treatment of GC patients.
Abstract: Background: Recent evidence demonstrates that pyroptosis-derived long non-coding RNAs (lncRNAs) have profound impacts on the initiation, progression, and microenvironment of tumors. However, the roles of pyroptosis-derived lncRNAs (PDLs) in gastric cancer (GC) remain elusive. Methods: We comprehensively analyzed the multi-omics data of 839 GC patients from three independent cohorts. The previous gene set enrichment analysis embedding algorithm was utilized to identify PDLs. A gene pair pipeline was developed to facilitate clinical translation via qualitative relative expression orders. The LASSO algorithm was used to construct and validate a pyroptosis-derived lncRNA pair prognostics signature (PLPPS). The associations between PLPPS and multi-omics alteration, immune profile, and pharmacological landscape were further investigated. Results: A total of 350 PDLs and 61,075 PDL pairs in the training set were generated. Cox regression revealed 15 PDL pairs associated with overall survival, which were utilized to construct the PLPPS model via the LASSO algorithm. The high-risk group demonstrated adverse prognosis relative to the low-risk group. Remarkably, genomic analysis suggested that the lower tumor mutation burden and gene mutation frequency (e.g., TTN, MUC16, and LRP1B) were found in the high-risk group patients. The copy number variants were not significantly different between the two groups. Additionally, the high-risk group possessed lower immune cell infiltration abundance and might be resistant to a few chemotherapeutic drugs (including cisplatin, paclitaxel, and gemcitabine). Conclusion: PDLs were closely implicated in the biological process and prognosis of GC, and our PLPPS model could serve as a promising tool to advance prognostic management and personalized treatment of GC patients.
9 citations
TL;DR: The roles of G SDME-driven programmed cell death in different diseases and the potential targeted therapies of GSDME are introduced to provide a foundation for future research.
Abstract: Gasdermin E (GSDME) is a member of the gasdermin protein family, which mediates programmed cell death including apoptosis and pyroptosis. Recently, it was suggested that GSDME is activated by chemotherapeutic drugs to stimulate pyroptosis of cancer cells and trigger anti-tumor immunity, which is identified as a tumor suppressor. However, GSDME-mediated pyroptosis contributes to normal tissue damage, leading to pathological inflammations. Inhibiting GSDME-mediated pyroptosis might be a potential target in ameliorating inflammatory diseases. Therefore, targeting GSDME is a promising option for the treatment of diseases in the future. In this review, we introduce the roles of GSDME-driven programmed cell death in different diseases and the potential targeted therapies of GSDME, so as to provide a foundation for future research.
6 citations
TL;DR: The potential of natural PKM2 inhibitors from natural products that are promising drug candidates for cancer therapy are highlighted and researchers are encouraged to evaluate the combinational effects between natural and synthetic PKM 2 inhibitors.
Abstract: Glycolysis is the primary source of energy for cancer growth and metastasis. The shift in metabolism from mitochondrial oxidative phosphorylation to aerobic glycolysis is called the Warburg effect. Cancer progression due to aerobic glycolysis is often associated with the activation of oncogenes or the loss of tumor suppressors. Therefore, inhibition of glycolysis is one of the effective strategies in cancer control. Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme overexpressed in breast, prostate, lung, colorectal, and liver cancers. Here, we discuss published studies regarding PKM2 inhibitors from natural products that are promising drug candidates for cancer therapy. We have highlighted the potential of natural PKM2 inhibitors for various cancer types. Moreover, we encourage researchers to evaluate the combinational effects between natural and synthetic PKM2 inhibitors. Also, further high‐quality studies are needed to firmly establish the clinical efficacy of natural products.
5 citations
References
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TL;DR: The GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer (IARC) as mentioned in this paper show that female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung cancer, colorectal (11 4.4%), liver (8.3%), stomach (7.7%) and female breast (6.9%), and cervical cancer (5.6%) cancers.
Abstract: This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
35,190 citations
TL;DR: The discovery of caspase-11/4/5 function in sensing intracellular lipopolysaccharide expands the spectrum of pyroptosis mediators and also reveals that pyroPTosis is not cell type specific.
1,611 citations
TL;DR: It is shown that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5), can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis, suggesting that casp enzyme activation can trigger necrosis by cleaving G SDME and offer new insights into cancer chemotherapy.
Abstract: Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide. The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity. GSDMD belongs to a gasdermin family that shares the pore-forming domain. The functions and mechanisms of activation of other gasdermins are unknown. Here we show that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5), can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis. After chemotherapy, cleavage of GSDME by caspase-3 induced pyroptosis in certain GSDME-expressing cancer cells. GSDME was silenced in most cancer cells but expressed in many normal tissues. Human primary cells exhibited GSDME-dependent pyroptosis upon activation of caspase-3 by chemotherapy drugs. Gsdme-/- (also known as Dfna5-/-) mice were protected from chemotherapy-induced tissue damage and weight loss. These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy.
1,458 citations
TL;DR: It is shown that the expression of enzymatically inactive CASP8(C362S) causes embryonic lethality in mice by inducing necroptosis and pyroptosis, and prevents tissue damage during embryonic development and adulthood in mice.
Abstract: Caspase-8 is the initiator caspase of extrinsic apoptosis(1,2) and inhibits necroptosis mediated by RIPK3 and MLKL. Accordingly, caspase-8 deficiency in mice causes embryonic lethality(3), which can be rescued by deletion of either Ripk3 or Mlkl(4-6). Here we show that the expression of enzymatically inactive CASP8(C362S) causes embryonic lethality in mice by inducing necroptosis and pyroptosis. Similar to Casp8(-/-) mice(3,7), Casp8(C362S/C362S) mouse embryos died after endothelial cell necroptosis leading to cardiovascular defects. MLKL deficiency rescued the cardiovascular phenotype but unexpectedly caused perinatal lethality in Casp8(C362S/C362S) mice, indicating that CASP8(C362S) causes necroptosis-independent death at later stages of embryonic development. Specific loss of the catalytic activity of caspase-8 in intestinal epithelial cells induced intestinal inflammation similar to intestinal epithelial cell-specific Casp8 knockout mice(8). Inhibition of necroptosis by additional deletion of Mlkl severely aggravated intestinal inflammation and caused premature lethality in Mlkl knockout mice with specific loss of caspase-8 catalytic activity in intestinal epithelial cells. Expression of CASP8(C362S) triggered the formation of ASC specks, activation of caspase-1 and secretion of IL-1 beta. Both embryonic lethality and premature death were completely rescued in Casp8(C362S/C362S)Mlkl(-/-)Asc(-/-) or Casp8(C362S/C362S)Mlkl(-/-)Casp1(-/-) mice, indicating that the activation of the inflammasome promotes CASP8(C362S)-mediated tissue pathology when necroptosis is blocked. Therefore, caspase-8 represents the molecular switch that controls apoptosis, necroptosis and pyroptosis, and prevents tissue damage during embryonic development and adulthood.
469 citations
TL;DR: Findings identify a non-immune checkpoint function of PD-L1 and provide an unexpected concept that GSDMC/Caspas-8 mediates non-canonical pyroptosis pathway in cancer cells, causing tumor necrosis.
Abstract: Although pyroptosis is critical for macrophages against pathogen infection, its role and mechanism in cancer cells remains unclear. PD-L1 has been detected in the nucleus, with unknown function. Here we show that PD-L1 switches TNFα-induced apoptosis to pyroptosis in cancer cells, resulting in tumour necrosis. Under hypoxia, p-Stat3 physically interacts with PD-L1 and facilitates its nuclear translocation, enhancing the transcription of the gasdermin C (GSDMC) gene. GSDMC is specifically cleaved by caspase-8 with TNFα treatment, generating a GSDMC N-terminal domain that forms pores on the cell membrane and induces pyroptosis. Nuclear PD-L1, caspase-8 and GSDMC are required for macrophage-derived TNFα-induced tumour necrosis in vivo. Moreover, high expression of GSDMC correlates with poor survival. Antibiotic chemotherapy drugs induce pyroptosis in breast cancer. These findings identify a non-immune checkpoint function of PD-L1 and provide an unexpected concept that GSDMC/caspase-8 mediates a non-canonical pyroptosis pathway in cancer cells, causing tumour necrosis.
431 citations