Therapeutic inhibition of PPARα-HIF1α-PGK1 signaling targets leukemia stem and progenitor cells in acute myeloid leukemia

Zhou, Hui; Jiang, Yuelong; Huang, Yuetin; Zhong, Min; Qin, Dongmei; Xie, Chendi; Pan, Guangchao; Tan, Jinshui; Deng, Manman; Zhao, Haitao; Zhou, Yong; Tang, Yuan; Lai, Qian; Fang, Zhihong; Luo, Yiming; Jiang, Yunxia; Xu, Bing; Zha, Jun

doi:10.1016/j.canlet.2022.215997

Cited by 19 publications

(7 citation statements)

References 38 publications

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“…Many previous studies have shown that PGK1 has a function in malignant tumors. Therapeutic inhibition of PPARα-HIF1α-PGK1 signaling targeting acute myeloid leukemia according to Jie Zha et al ( 44 ). Overexpression of PGK1 in prostate cancer cells has been reported to increase cell metastasis through the CXCR4/CXCL12 axis ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

Exploring the role of sphingolipid-related genes in clinical outcomes of breast cancer

et al. 2023

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BackgroundDespite tremendous advances in cancer research, breast cancer (BC) remains a major health concern and is the most common cancer affecting women worldwide. Breast cancer is a highly heterogeneous cancer with potentially aggressive and complex biology, and precision treatment for specific subtypes may improve survival in breast cancer patients. Sphingolipids are important components of lipids that play a key role in the growth and death of tumor cells and are increasingly the subject of new anti-cancer therapies. Key enzymes and intermediates of sphingolipid metabolism (SM) play an important role in regulating tumor cells and further influencing clinical prognosis.MethodsWe downloaded BC data from the TCGA database and GEO database, on which we performed in depth single-cell sequencing analysis (scRNA-seq), weighted co-expression network analysis, and transcriptome differential expression analysis. Then seven sphingolipid-related genes (SRGs) were identified using Cox regression, least absolute shrinkage, and selection operator (Lasso) regression analysis to construct a prognostic model for BC patients. Finally, the expression and function of the key gene PGK1 in the model were verified by in vitro experiments.ResultsThis prognostic model allows for the classification of BC patients into high-risk and low-risk groups, with a statistically significant difference in survival time between the two groups. The model is also able to show high prediction accuracy in both internal and external validation sets. After further analysis of the immune microenvironment and immunotherapy, it was found that this risk grouping could be used as a guide for the immunotherapy of BC. The proliferation, migration, and invasive ability of MDA-MB-231 and MCF-7 cell lines were dramatically reduced after knocking down the key gene PGK1 in the model through cellular experiments.ConclusionThis study suggests that prognostic features based on genes related to SM are associated with clinical outcomes, tumor progression, and immune alterations in BC patients. Our findings may provide insights for the development of new strategies for early intervention and prognostic prediction in BC.

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Section: Discussionmentioning

confidence: 99%

Exploring the role of sphingolipid-related genes in clinical outcomes of breast cancer

et al. 2023

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“…Furthermore, this study demonstrated that venetoclax combined with chiglitazar resulted in synergistic lethality to primary CD34 + AML cells while largely sparing their normal counterparts. While the exact mechanism for such selectivity remains unclear, one possible explanation is the differential expression of PPARα between HSCs and CD34 + AML cells [ 48 ]. The efficacy of this regimen was further validated in a PDX model.…”

Section: Discussionmentioning

confidence: 99%

Bcl-2 inhibition combined with PPARα activation synergistically targets leukemic stem cell-like cells in acute myeloid leukemia

Xie,

Zhou,

Qin

et al. 2023

Cell Death Dis

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Persistence of leukemic stem cells (LSCs) is one of the determining factors to acute myeloid leukemia (AML) treatment failure and responsible for the poor prognosis of the disease. Hence, novel therapeutic strategies that target LSCs are crucial for treatment success. We investigated if targeting Bcl-2 and peroxisome proliferator activated receptor α (PPARα), two distinct cell survival regulating mechanisms could eliminate LSCs. This study demonstrate that the Bcl-2 inhibitor venetoclax combined with the PPARα agonist chiglitazar resulted in synergistic killing of LSC-like cell lines and CD34+ primary AML cells while sparing their normal counterparts. Furthermore, the combination regimen significantly suppressed AML progression in patient-derived xenograft (PDX) mouse models. Mechanistically, chiglitazar-mediated PPARα activation inhibited the transcriptional activity of the PIK3AP1 gene promoter and down-regulated the PI3K/Akt signaling pathway and anti-apoptotic Bcl-2 proteins, leading to cell proliferation inhibition and apoptosis induction, which was synergized with venetoclax. These findings suggest that combinatorial Bcl-2 inhibition and PPARα activation selectively eliminates AML cells in vivo and vitro, representing an effective therapy for patients with relapsed and refractory AML.

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“…The upregulation of this gene was also found to activate the NF-κB pathway, and its downregulation led to a decrease in the proliferation and an increase in the inhibition of apoptosis in AML leukemic cell lines [ 49 ]. c-MYC has been extensively associated with oncogenic functions, carcinogenesis, angiogenesis, chemoresistance, and many more cancer-promoting roles [ 54 , 55 ]. c-MYC has also been found to be a potential therapeutic target in leukemia, along with other cancer types [ 56 , 57 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

Investigation into the Role of Long-Non-Coding RNA MIAT in Leukemia

Ostini,

Mourtada-Maarabouni

2023

ncRNA

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Myocardial Infarction Associated Transcript (MIAT) is a nuclear long non-coding RNA (LncRNA) with four different splicing variants. MIAT dysregulation is associated with carcinogenesis, mainly acting as an oncogene regulating cellular growth, invasion, and metastasis. The aim of the current study is to investigate the role of MIAT in the regulation of T and chronic myeloid leukemic cell survival. To this end, MIAT was silenced using MIAT-specific siRNAs in leukemic cell lines, and functional assays were performed thereafter. This investigation also aims to investigate the effects of MIAT silencing on the expression of core genes involved in cancer. Functional studies and gene expression determination confirm that MIAT knockdown not only affects short- and long-term survival and the apoptosis of leukemic cells but also plays a pivotal role in the alteration of key genes involved in cancer, including c-MYC and HIF-1A. Our observations suggest that MIAT could act as an oncogene and it has the potential to be used not only as a reliable biomarker for leukemia, but also be employed for prognostic and therapeutic purposes.

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Therapeutic inhibition of PPARα-HIF1α-PGK1 signaling targets leukemia stem and progenitor cells in acute myeloid leukemia

Cited by 19 publications

References 38 publications

Exploring the role of sphingolipid-related genes in clinical outcomes of breast cancer

Exploring the role of sphingolipid-related genes in clinical outcomes of breast cancer

Bcl-2 inhibition combined with PPARα activation synergistically targets leukemic stem cell-like cells in acute myeloid leukemia

Investigation into the Role of Long-Non-Coding RNA MIAT in Leukemia

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