A functional screen with metformin identifies microRNAs that regulate metabolism in colorectal cancer cells.
A functional screen with metformin identifies microRNAs that regulate metabolism in colorectal cancer cells.
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DOI：
10.1038/s41598-022-06587-9
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发表时间：
2022-02-21
影响因子：
4.6
通讯作者：
Michael MZ
中科院分区：
文献类型：
--
作者：
Orang A;Ali SR;Petersen J;McKinnon RA;Aloia AL;Michael MZ
Metalloprotein抑制氧化磷酸化，可用于剖析结直肠癌（CRC）细胞中的代谢途径。二甲双胍以剂量依赖性方式抑制CRC细胞增殖。调节代谢的microRNA可以通过其改变二甲双胍对CRC细胞增殖的影响的能力来鉴定。使用合成micoRNA（miRNA）文库的无偏高通量功能筛选来鉴定影响CRC细胞中二甲双胍应答的miRNA。选定命中的实验验证鉴定了通过调节增殖、凋亡、细胞周期和直接代谢破坏使CRC细胞对二甲双胍敏感的miRNA。在通过功能筛选鉴定的8种二甲双胍致敏miRNA中，miR-676- 3 p与二甲双胍联合时具有促凋亡和细胞周期阻滞活性，而其他miRNA（miR-18 b-5 p、miR-145- 3 p、miR-376 b-5 p和miR-718）与二甲双胍联合时主要导致细胞周期阻滞。miRNA和二甲双胍对CRC细胞代谢的联合作用的研究显示，miR-18 b-5 p、miR-145- 3 p、miR-376 b-5 p、miR-676- 3 p和miR-718仅影响糖酵解，而miR-1181仅调节CRC呼吸。MicroRNA可以使CRC细胞对二甲双胍的抗增殖作用敏感。识别相关的miRNA靶点可以设计创新的治疗策略。
Metformin inhibits oxidative phosphorylation and can be used to dissect metabolic pathways in colorectal cancer (CRC) cells. CRC cell proliferation is inhibited by metformin in a dose dependent manner. MicroRNAs that regulate metabolism could be identified by their ability to alter the effect of metformin on CRC cell proliferation. An unbiased high throughput functional screen of a synthetic micoRNA (miRNA) library was used to identify miRNAs that impact the metformin response in CRC cells. Experimental validation of selected hits identified miRNAs that sensitize CRC cells to metformin through modulation of proliferation, apoptosis, cell-cycle and direct metabolic disruption. Among eight metformin sensitizing miRNAs identified by functional screening, miR-676-3p had both pro-apoptotic and cell cycle arrest activity in combination with metformin, whereas other miRNAs (miR-18b-5p, miR-145-3p miR-376b-5p, and miR-718) resulted primarily in cell cycle arrest when combined with metformin. Investigation of the combined effect of miRNAs and metformin on CRC cell metabolism showed that miR-18b-5p, miR-145-3p, miR-376b-5p, miR-676-3p and miR-718 affected glycolysis only, while miR-1181 only regulated CRC respiration. MicroRNAs can sensitize CRC cells to the anti-proliferative effects of metformin. Identifying relevant miRNA targets may enable the design of innovative therapeutic strategies.
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癌细胞对葡萄糖限制和双胍类药物敏感性的代谢决定因素。
影响因子：
64.8
作者：
Birsoy, Kivanc;Possemato, Richard;Lorbeer, Franziska K.;Bayraktar, Erol C.;Thiru, Prathapan;Yucel, Burcu;Wang, Tim;Chen, Walter W.;Clish, Clary B.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
5.6
作者：
Bertoli G;Cava C;Castiglioni I
通讯作者：
Castiglioni I
影响因子：
14.9
作者：
Backes C;Kehl T;Stöckel D;Fehlmann T;Schneider L;Meese E;Lenhof HP;Keller A
通讯作者：
Keller A
DOI：
10.1083/jcb.200403069
发表时间：
2004-07-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harrington LS;Findlay GM;Gray A;Tolkacheva T;Wigfield S;Rebholz H;Barnett J;Leslie NR;Cheng S;Shepherd PR;Gout I;Downes CP;Lamb RF
通讯作者：
Lamb RF
影响因子：
4.6
作者：
Bjork, Johanna K.;Sandqvist, Anton;Sistonen, Lea
通讯作者：
Sistonen, Lea