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Diethyldithiocarbamate-copper complex (CuET) inhibits colorectal cancer progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway
Oncogenesis ( IF 5.9 ) Pub Date : 2021-01-08 , DOI: 10.1038/s41389-020-00295-7
Xin Huang 1, 2 , Yichao Hou 1, 2 , Xiaoling Weng 3 , Wenjing Pang 1, 2 , Lidan Hou 1, 2 , Yu Liang 1, 2 , Yu Wang 1, 2 , Leilei Du 3 , Tianqi Wu 3 , Mengfei Yao 3 , Jianhua Wang 3 , Xiangjun Meng 1, 2
Affiliation  

Exploring novel anticancer drugs to optimize the efficacy may provide a benefit for the treatment of colorectal cancer (CRC). Disulfiram (DSF), as an antialcoholism drug, is metabolized into diethyldithiocarbamate-copper complex (CuET) in vivo, which has been reported to exert the anticancer effects on various tumors in preclinical studies. However, little is known about whether CuET plays an anti-cancer role in CRC. In this study, we found that CuET had a marked effect on suppressing CRC progression both in vitro and in vivo by reducing glucose metabolism. Mechanistically, using RNA-seq analysis, we identified ALDH1A3 as a target gene of CuET, which promoted cell viability and the capacity of clonal formation and inhibited apoptosis in CRC cells. MicroRNA (miR)-16-5p and 15b-5p were shown to synergistically regulate ALDH1A3, which was negatively correlated with both of them and inversely correlated with the survival of CRC patients. Notably, using co-immunoprecipitation followed with mass spectrometry assays, we identified PKM2 as a direct downstream effector of ALDH1A3 that stabilized PKM2 by reducing ubiquitination. Taken together, we disclose that CuET treatment plays an active role in inhibiting CRC progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis–mediated aerobic glycolysis pathway.



中文翻译:


二乙基二硫代氨基甲酸酯-铜复合物 (CuET) 通过 miR-16-5p 和 15b-5p/ALDH1A3/PKM2 轴介导的有氧糖酵解途径抑制结直肠癌进展



探索新型抗癌药物以优化疗效可能会为结直肠癌(CRC)的治疗带来益处。双硫仑(DSF)作为一种抗酒精药物,在体内代谢为二乙基二硫代氨基甲酸铜复合物(CuET),临床前研究报道其对多种肿瘤具有抗癌作用。然而,CuET 是否在结直肠癌中发挥抗癌作用尚不清楚。在这项研究中,我们发现 CuET 通过降低葡萄糖代谢,在体外和体内对抑制 CRC 进展具有显着效果。从机制上讲,通过RNA-seq分析,我们确定ALDH1A3是CuET的靶基因,它可以促进细胞活力和克隆形成的能力,并抑制CRC细胞的凋亡。 MicroRNA (miR)-16-5p 和 15b-5p 被证明可以协同调节 ALDH1A3,与两者呈负相关,并与 CRC 患者的生存呈负相关。值得注意的是,通过免疫共沉淀和质谱分析,我们确定 PKM2 是 ALDH1A3 的直接下游效应子,通过减少泛素化来稳定 PKM2。综上所述,我们发现 CuET 治疗通过 miR-16-5p 和 15b-5p/ALDH1A3/PKM2 轴介导的有氧糖酵解途径在抑制 CRC 进展中发挥积极作用。

更新日期:2021-01-08
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