2. Academic Validation
  3. Antitumor Effect of Simvastatin in Combination With DNA Methyltransferase Inhibitor on Gastric Cancer via GSDME-Mediated Pyroptosis

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

  • Front Pharmacol. 2022 Apr 20:13:860546. doi: 10.3389/fphar.2022.860546.
Ying Xia 1 2 3 4,  Yong Jin 1 4,  Daxiang Cui 5,  Xia Wu 6,  Cunfeng Song 5,  Weilin Jin 5 7,  Hai Huang 1 4
Affiliations

Affiliations

  • 1 Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
  • 2 Department of Pathophysiology, School of Basic Medical Science, Guizhou Medical University, Guiyang, China.
  • 3 Department of Clinical Laboratory, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China.
  • 4 School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, China.
  • 5 Shanghai Engineering Research Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Institute of Nano Biomedicine and Engineering, Shanghai Jiao Tong University, Shanghai, China.
  • 6 Guizhou Provincial People's Hospital, Guiyang, China.
  • 7 Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, China.
PMID: 35517821 DOI: 10.3389/fphar.2022.860546
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.

Keywords

DNA methyltransferase inhibitor; GSDME; gastric cancer; pyroptosis; simvastatin.

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