2. Academic Validation
  3. Induction of IFIT1/IFIT3 and inhibition of Bcl-2 orchestrate the treatment of myeloma and leukemia via pyroptosis

Induction of IFIT1/IFIT3 and inhibition of Bcl-2 orchestrate the treatment of myeloma and leukemia via pyroptosis

  • Cancer Lett. 2024 Mar 8:216797. doi: 10.1016/j.canlet.2024.216797.
Yuanming He 1,  Shuoyi Jiang 1,  Yaoli Cui 1,  Jingpei Liang 1,  Yueya Zhong 1,  Yuening Sun 1,  Michael F Moran 2,  Zhenqian Huang 1,  Guisong He 3,  Xinliang Mao 4
Affiliations

Affiliations

  • 1 The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.
  • 2 The Department of Molecular Genetics, The University of Toronto, Toronto, ON, M5G 0A4, Canada; Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
  • 3 Department of Orthopedics, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
  • 4 The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China. Electronic address: [email protected].
PMID: 38462032 DOI: 10.1016/j.canlet.2024.216797
Abstract

Induction of Pyroptosis is proposed as a promising strategy for the treatment of hematological malignancies, but little is known. In the present study, we find clioquinol (CLQ), an Anti-parasitic drug, induces striking myeloma and leukemia cell Pyroptosis on a drug screen. RNA sequencing reveals that the interferon-inducible genes IFIT1 and IFIT3 are markedly upregulated and are essential for CLQ-induced GSDME activation and cell Pyroptosis. Specifically, IFIT1 and IFIT3 form a complex with Bax and N-GSDME therefore directing N-GSDME translocalization to mitochondria and increasing mitochondrial membrane permeabilization and triggering Pyroptosis. Furthermore, venetoclax, an activator of Bax and an inhibitor of Bcl-2, displays strikingly synergistic effects with CLQ against leukemia and myeloma via Pyroptosis. This study thus reveals a novel mechanism for mitochondrial GSDME in Pyroptosis and it also illustrates that induction of IFIT1/T3 and inhibition of Bcl-2 orchestrate the treatment of leukemia and myeloma via Pyroptosis.

Keywords

Bcl-2; Clioquinol; Gasdermin E; Interferon-inducible genes; Mitochondria; Pyroptosis.

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