Therapeutic inhibition of PPARα-HIF1α-PGK1 signaling targets leukemia stem and progenitor cells in acute myeloid leukemia. (1st February 2023)

• Record Type: Journal Article
• Authors: Zhou, Hui; Jiang, Yuelong; Huang, Yuetin; Zhong, Mengya; Qin, Dongmei; Xie, Chendi; Pan, Guangchao; Tan, Jinshui; Deng, Manman; Zhao, Haijun; Zhou, Yong; Tang, Yuanfang; Lai, Qian; Fang, Zhihong; Luo, Yiming; Jiang, Yirong; Xu, Bing; Zha, Jie
• Is Part Of: Cancer letters. Volume 554(2023)
• Publication Date: 2023-02-01
• Subjects: Leukemia stem and progenitor cells -- Acute myeloid leukemia -- Glycolysis -- PPARα -- Chiglitazar -- HIF1α; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2022.215997
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Treatment of acute myeloid leukemia (AML) with chemotherapeutic agents fails to eliminate leukemia stem cells (LSC)，and thus patients remain at high risk for relapse. Therefore, the identification of agents that target LSC is an important consideration for the development of new therapies. Enhanced glycolysis in LSC contributes to the aggressiveness of AML, which is difficult to be targeted. In this study, we showed that targeting peroxisome-proliferator-activated receptor α (PPARα), a ligand-activated transcription factor by chiglitazar provided a promising therapeutic approach. We first identified that chiglitazar reduced cell viability and proliferation of the leukemia stem-like cells population in AML. Treatment with chiglitazar blocked the ubiquitination of PPARα and increased its expression, resulting in the inhibition of glucose metabolism and apoptosis of AML cells. Consistent with its anti-leukemia stem-like cells activity in vitro, chiglitazar treatment in vivo resulted in the significant killing of leukemia stem-like cells as demonstrated in AML patient-derived xenograft (PDX) models. Mechanistically, PPARα overexpression inhibited the expression and promoter activity of PGK1 through blocking HIF1-α interaction on the PGK1 promoter. Thus, we concluded that targeting PPARα may serve as a novel approach for enhancing stem and progenitor cells elimination in AML. Highlights: Chiglitazar exhibited cytotoxicity against leukemic stem-like cells and primary CD34 + AML cells in vitro and in vivo. Chiglitazar increased the expression of PPARα by inhibition of ubiquitin-proteasome system in leukemic stem-like cells. Chiglitazar inhibited the transcriptional activity of the HIF1α and reduced glucose metabolism in leukemic stem-like cells. PPARα interacted with HIF1α and inhibited its recruitment to the PGK1 gene promoter in leukemic stem-like cells.