GW4064 enhances the chemosensitivity of colorectal cancer to oxaliplatin by inducing pyroptosis

Guo, Jing; Zheng, Jianbao; Mu, Mingchao; Chen, Zilu; Xu, Zhengshui; Zhao, Chenye; Yang, Kui; Xiao, Qin; Sun, Xuejun; Yu, Ji Hee

doi:10.1016/j.bbrc.2021.02.043

Cited by 47 publications

(36 citation statements)

References 22 publications

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“…Additionally, there was a non-significant trend toward improved PFS and OS in FXR high-expression group as compared with FXR low-expression group with the same treatment. Consistent with the present findings, previous studies have reported that FXR activation enhanced the chemo-sensitivity of biliary tract and colorectal cancer cells to oxaliplatin and cisplatin, respectively ( 38 , 39 ).…”

Section: Discussionsupporting

confidence: 93%

High farnesoid X receptor expression predicts favorable clinical outcomes in PD‑L1^low/negative non‑small cell lung cancer patients receiving anti‑PD‑1‑based chemo‑immunotherapy

Wang

Shang

et al. 2022

Int J Oncol

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Anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1)-directed immunotherapy has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). However, predictive biomarkers are still lacking, particularly in identifying PD-L1 low/negative patients who will benefit from immunotherapy. It was previously reported that farnesoid X receptor (FXR) downregulated PD-L1 expression in NSCLC, and that FXR high PD-L1 low mouse Lewis lung carcinoma tumors showed an increased susceptibility to PD-1 blockade compared with mock tumors. At present, whether the FXR high PD-L1 low phenotype predicts clinical response to immunotherapy in patients with NSCLC remains unclear. Herein, a retrospective study was conducted to examine the expression levels of FXR, PD-L1 and CD8 + T cells by immunohistochemistry in a cohort of 149 patients with NSCLC receiving anti-PD-1-based chemo-immunotherapy. The results revealed that high FXR and PD-L1 expression levels were associated with higher objective response rates (ORR) in all patients. High PD-L1 expression also indicated superior progression-free survival (PFS). Interestingly, an inverse correlation was identified between FXR and PD-L1 expression in specimens with NSCLC. Subgroup analysis revealed that high FXR expression was associated with a higher ORR, as well as longer PFS and overall survival (OS) in PD-L1 low patients. Cox multivariate analysis revealed that high FXR expression was an independent predictor for PFS and OS in PD-L1 low patients. Tumor microenvironment evaluation revealed a statistically significant decrease of infiltrating CD8 + T cells in FXR high specimens with NSCLC. Overall, the present study proposed an FXR high PD-L1 low signature as a candidate predictor of response to anti-PD-1-based chemo-immunotherapy in PD-L1 low/negative patients with NSCLC, providing evidence that could be used to broaden the patients benefitting from immunotherapy.

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Section: Discussionsupporting

confidence: 93%

High farnesoid X receptor expression predicts favorable clinical outcomes in PD‑L1^low/negative non‑small cell lung cancer patients receiving anti‑PD‑1‑based chemo‑immunotherapy

Wang

Shang

et al. 2022

Int J Oncol

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“…Targeting pyroptosis is considered a novel enrichment to our cancer-fighting arsenal ( Guo et al, 2021 ; Yuan et al, 2021 ) and GSDME is the newly recognized executor of pyroptosis ( Xia et al, 2020 ). It has been reported that dihydroartemisinin (DHA), a conventional drug to kill malaria parasites, can induce pyroptosis of esophageal squamous cell carcinoma (ESCC) cells via PKM2 caspase-8/3-GSDME pathway, providing a potential therapeutic agent for the treatment of ESCC ( Jiang et al, 2021b ).…”

Section: Discussionmentioning

confidence: 99%

Antitumor Effect of Simvastatin in Combination With DNA Methyltransferase Inhibitor on Gastric Cancer via GSDME-Mediated Pyroptosis

Xia

Cui

et al. 2022

Front. Pharmacol.

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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.

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“…Pyroptosis, as a newly discovered type of programmed cell death, has recently attracted increasing attention in the field of cancer biological research ( Du et al, 2021 ; Loveless et al, 2021 ). Increasing evidence has shown the important dual role and mechanisms of pyroptosis involved in the development and treatment of various cancers ( Cai et al, 2021 ; Guo et al, 2021c ; Shao et al, 2021 ; Ye et al, 2021 ; Zhang et al, 2021 ). On the one hand, pyroptosis can cause excessive inflammation in the body, release many inflammatory cytokines, and change the immune microenvironment, thereby promoting the generation and development of tumors ( Karki and Kanneganti, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

The Pyroptosis-Related Long Noncoding RNA Signature Predicts Prognosis and Indicates Immunotherapeutic Efficiency in Hepatocellular Carcinoma

Wang

Yang

Sun

et al. 2022

Front. Cell Dev. Biol.

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Pyroptosis was recently demonstrated to be an inflammatory form of gasdermin-regulated programmed cell death characterized by cellular lysis and the release of several proinflammatory factors and participates in tumorigenesis. However, the effects of pyroptosis-related long noncoding RNAs (lncRNAs) on hepatocellular carcinoma (HCC) have not yet been completely elucidated. Based on the regression coefficients of ZFPM2-AS1, KDM4A-AS1, LUCAT1, NRAV, CRYZL2P-SEC16B, AL031985.3, SNHG4, AL049840.5, AC008549.1, MKLN1-AS, AC099850.3, and LINC01224, HCC patients were classified into a low- or high-risk group. The high-risk score according to pyroptosis-related lncRNA signature was significantly associated with poor overall survival even after adjusting for age and clinical stage. Receiver operating characteristic curves and principal component analysis further supported the accuracy of the model. Our study revealed that a higher pyroptosis-related lncRNA risk score was significantly associated with tumor staging, pathological grade, and tumor-node-metastasis stages. The nomogram incorporating the pyroptosis-related lncRNA risk score and clinicopathological factors demonstrated good accuracy. Furthermore, we observed distinct tumor microenvironment cell infiltration characteristics between high- and low-risk tumors. Notably, based on the risk model, we found that the risk score is closely related to the expression of immune checkpoint genes, immune subtypes of tumors, and the sensitivity of HCC to chemotherapy drugs and immunotherapy. In conclusion, our novel risk score of pyroptosis-related lncRNA can serve as a promising prognostic biomarker for HCC patients and provide help for HCC patients to guide precision drug treatment and immunotherapy.

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GW4064 enhances the chemosensitivity of colorectal cancer to oxaliplatin by inducing pyroptosis

Cited by 47 publications

References 22 publications

High farnesoid X receptor expression predicts favorable clinical outcomes in PD‑L1^low/negative non‑small cell lung cancer patients receiving anti‑PD‑1‑based chemo‑immunotherapy

High farnesoid X receptor expression predicts favorable clinical outcomes in PD‑L1^low/negative non‑small cell lung cancer patients receiving anti‑PD‑1‑based chemo‑immunotherapy

Antitumor Effect of Simvastatin in Combination With DNA Methyltransferase Inhibitor on Gastric Cancer via GSDME-Mediated Pyroptosis

The Pyroptosis-Related Long Noncoding RNA Signature Predicts Prognosis and Indicates Immunotherapeutic Efficiency in Hepatocellular Carcinoma

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GW4064 enhances the chemosensitivity of colorectal cancer to oxaliplatin by inducing pyroptosis

Cited by 47 publications

References 22 publications

High farnesoid X receptor expression predicts favorable clinical outcomes in PD‑L1low/negative non‑small cell lung cancer patients receiving anti‑PD‑1‑based chemo‑immunotherapy

High farnesoid X receptor expression predicts favorable clinical outcomes in PD‑L1low/negative non‑small cell lung cancer patients receiving anti‑PD‑1‑based chemo‑immunotherapy

Antitumor Effect of Simvastatin in Combination With DNA Methyltransferase Inhibitor on Gastric Cancer via GSDME-Mediated Pyroptosis

The Pyroptosis-Related Long Noncoding RNA Signature Predicts Prognosis and Indicates Immunotherapeutic Efficiency in Hepatocellular Carcinoma

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High farnesoid X receptor expression predicts favorable clinical outcomes in PD‑L1^low/negative non‑small cell lung cancer patients receiving anti‑PD‑1‑based chemo‑immunotherapy

High farnesoid X receptor expression predicts favorable clinical outcomes in PD‑L1^low/negative non‑small cell lung cancer patients receiving anti‑PD‑1‑based chemo‑immunotherapy