1. Academic Validation
  2. Dihydroartemisinin mediating PKM2-caspase-8/3-GSDME axis for pyroptosis in esophageal squamous cell carcinoma

Dihydroartemisinin mediating PKM2-caspase-8/3-GSDME axis for pyroptosis in esophageal squamous cell carcinoma

  • Chem Biol Interact. 2021 Dec 1;350:109704. doi: 10.1016/j.cbi.2021.109704.
Mingxia Jiang 1 Yiming Wu 1 Ling Qi 1 Lisha Li 1 Dongfeng Song 1 Junqing Gan 1 Yanjing Li 2 Xiaodong Ling 3 Chengxin Song 4
Affiliations

Affiliations

  • 1 Department of Gastroenterology Oncology, Harbin Medical University Cancer Hospital, 150 Haping St, Nangang District, Harbin, Heilongjiang, 150081, PR China.
  • 2 Department of Gastroenterology Oncology, Harbin Medical University Cancer Hospital, 150 Haping St, Nangang District, Harbin, Heilongjiang, 150081, PR China. Electronic address: liyanjing_hmu@hrbmu.edu.cn.
  • 3 Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, 150081, China. Electronic address: lxdhmu@163.com.
  • 4 Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China. Electronic address: scxqy@163.com.
Abstract

Pyroptosis is a novel type of pro-inflammatory programmed cell death that has been strongly reported to be related to inflammation, immune, and Cancer. Dihydroartemisinin (DHA) has good anti-tumor properties. However, the exact mechanism by which DHA induces Pyroptosis to inhibit esophageal squamous cell carcinoma (ESCC) remains unclear. After applying DHA treatment to ESCC, we found that 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. Meanwhile, it was accompanied by an increased release of LDH and inflammatory factors (IL-18 and IL-1β). Both knockdown of GSDME and application of Caspase-8/3 specific inhibitors (z-ITED-FMK/Ac-DEVD-CHO) significantly inhibited DHA-induced Pyroptosis. However, the former did not affect the activation of Caspase-3. In contrast, overexpression of PKM2 inhibited Caspase-8/3 activation as well as GSDME-N production. Furthermore, both si-GSDME and OE-PKM2 inhibited DHA-induced Pyroptosis in vivo and in vitro. Therefore, the results suggest that DHA can induce Pyroptosis of ESCC cells via the PKM2-caspase-8/3-GSDME pathway. Implication: In this study, we identified new mechanism of DHA in inhibiting ESCC development and progression, and provide a potential therapeutic agent for the treatment of ESCC.

Keywords

Dihydroartemisinin; ESCC; Gasdermin E; Pyroptosis; Pyruvate kinase M2.

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