ACTA PHARMACOLOGICA SINICA
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2024
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IF 6.9
Xia Rui-xue,Zou Pei-chen,Xie Jun-ting,Tang Ya-bin,Gong Miao-miao,Fan Fu,Aihemaiti Ayinazhaer,Liu Yu-qing,Shen Ying,Zhou Bin-bing S.,Zhu Liang,Lei Hui-min
RAS is the most frequently mutated oncoprotein for cancer driving. Understanding of RAS biology and discovery of druggable lynchpins in RAS pathway is a prerequisite for targeted therapy of RAS-mutant cancers. The recent identification of KRAS G12C inhibitor breaks the “undruggable” curse on RAS and has changed the therapy paradigm of KRAS-mutant cancers. However, KRAS mutations, let alone KRAS G12C mutation, account for only part of RAS-mutated cancers. Targeted therapies for cancers harboring other RAS mutations remain the urgent need. In this study we explored the pivotal regulatory molecules that allow for broad inhibition of RAS mutants. By comparing the expression levels of nucleotide pyrophosphatase (NPPS) in a panel of cell lines and the functional consequence of increased NPPS expression in RAS-mutant cells, we demonstrated that cancer cells with various kinds of RAS mutations depended on NPPS for growth and survival, and that this dependence conferred a vulnerability of RAS-mutant cancer to treatment of NPPS inhibition. RAS-mutant cells, compared with RAS-wildtype cells, bored and required an upregulation of NPPS. Transcriptomics and metabolomics analyses revealed a NPPS-dependent hyperglycolysis in RAS-mutant cells. We demonstrated that NPPS promoted glucose-derived glycolytic intermediates in RAS-mutant cells by enhancing its interaction with hexokinase 1 (HK1), the enzyme catalyzing the first committed step of glycolysis. Pharmacological inhibition of NPPS-HK1 axis using NPPS inhibitor Enpp-1-IN-1 or HK1 inhibitor 2-deoxyglucose (2-DG), or genetic interfere with NPPS suppressed RAS-mutant cancers in vitro and in vivo. In conclusion, this study reveals an unrecognized mechanism and druggable lynchpin for modulation of pan-mutant-RAS pathway, proposing a new potential therapeutic approach for treating RAS-mutant cancers.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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DOI
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
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2024
·Vol. 81
·期 1
·1-14
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IF 6.2
Ren Xuan,Huang Shihai,Xu Jianchun,Xue Qingsong,Xu Tairan,Shi Deshun,Ma Shinan,Li Xiangping
BRG1 has been found to promote the generation of induced pluripotent stem cells (iPSCs) by regulating epigenetic modifications or binding to transcription factors, however, the role of BRG1 on the cellular metabolism during reprogramming has not been reported. In this study, we found that BRG1 improved the efficiency of porcine iPSC generation, and upregulated the expression of pluripotency-related factors. Further analysis revealed that BRG1 promoted cellular glycolysis, and increased levels of glycolysis-related metabolites. It enhanced the transcriptional activity of glycolysis-related gene HK2, PKM2, and PFK-1 promoters, and decreased the enrichment of H3K9me3 in glycolysis- and pluripotency-related gene promoters. BRG1 also increased the phosphorylation level at the Ser473 site of AKT protein. The specific PI3K/AKT signaling pathway inhibitor, LY294002, impaired the generation of porcine iPSCs, downregulated the expression of pluripotency-related factors, and inhibited cellular glycolysis, overexpressing BRG1 rescued those changes caused by LY294002 treatment. In addition, the glycolysis inhibitor 2-DG and BRG1 inhibitor PFI-3 had similar effects to LY294002. The above results suggest that overexpression of BRG1 promotes the generation of porcine iPSCs by facilitating glycolytic reprogramming through the PI3K/AKT signaling pathway.
研究领域:
干细胞生物学
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代谢
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表观遗传学
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细胞重编程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF INDUSTRIAL AND ENGINEERING CHEMISTRY
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2022
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IF 6.76
Mengchao Ding,Xiaoying Kong,Weiyan Chen,Lei Yan,He Huang,Zunzhou Lv,Peng Jiang,Ali Mu,Congcong Huang,Jinsheng Shi
Single cancer starvation therapy (ST) strategy can’t achieve satisfactory anti-tumor effect, mainly due to the diversified nutritional sources of tumor cells. Herein, [email protected] 2 @2-Deoxy-D-glucose(2-DG)-CaCO 3 -RGD nanoparticles (CADCR NPs) were prepared for three-pathway blocking for efficient starvation therapy as well as reinforced photothermal therapy (PTT) and chemodynamic therapy (CDT). After CADCR NPs were targeted to tumor cells, CaCO 3 was ruptured in the acidic environment, releasing Ca 2+ to chelate glutamine and cutting off the glutamine metabolic pathway of the tumor. 2-DG was also released from mesoporous SiO 2 and restrained the glycolytic pathway of tumor cells. In addition, under the thermal stimulus of near-infrared irradiation, axitinib was released from CuS NPs, which inhibited the proliferation of tumor blood vessels, ultimately inhibiting the aerobic respiratory pathway of tumor cells. Interestingly, CADCR NPs also showed potential to reshape the tumor microenvironment (TME) and promoted the transformation of macrophages from M2 to M1 type, increasing the expression of CD8+ T cells in the tumor site. In conclusion, CADCR NPs achieve severe tumor starvation by simultaneously interfering with three energy metabolic pathways, and further enhance tumor treatment with the aid of PTT, CDT, and TME improvement, which exhibits great potential for clinical cancer therapy.
研究领域:
癌症治疗
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纳米技术
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生物医学工程
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药学
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肿瘤微环境
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细胞代谢
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）