To explore mechanisms underlying the discrepancy in anti-tumor effects of metformin on pancreatic cancer cells PANC-1 under different glucose conditions. We cultured PANC-1 cells in 25 mM and 5 mM glucose media, then treated with or without metformin. It showed that metformin significantly inhibited proliferation and viability, induced apoptosis of PANC-1 cells, which was more pronounced in low-glucose than in high-glucose group. Metformin up-regulated the expression of miR-210-5p in low glucose, but not in high glucose. miR-210-5p mimic inhibited the viability of PANC-1 cells and further enhanced the inhibitory effect of metformin. miR-210-5p down-regulated the expression of PFKFB2, a predicted target gene of miR-210-5p, reduced the activity of PFK1 and LDH. Metformin significantly inhibited the expression of phosphorylation-PFKFB2(p-PFKFB2) in the low-glucose group and inhibited the LDH activity both in the low and high glucose groups, thus inhibiting anaerobic glycolysis and inducing energy stress. Cells in the high glucose group could make a compensatory adaptation to the energy stress induced by metformin through increasing glucose consumption. However, due to the limited glucose supply and high dependence on anaerobic glycolysis of cells in the low glucose group, they couldn’t make effective adaptive compensation. Therefore, cells in the low-glucose group were more vulnerable to the toxicity of metformin. In conclusion, the enhanced inhibitory effect of metformin on PANC-1 cells cultured in low glucose may be due to the up-regulation of the expression of miR-210-5p, then inhibiting anaerobic glycolytic flux and inducing energy stress via repressing the expression of p-PFKFB2 and activity of LDH.

Abbreviations

PC: pancreatic cancer; DM: diabetes mellitus; PFKFB2: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase2; PFK1: phosphofructokinases; LDH: lactate dehydrogenase; F-2,6-BP: fructose 2,6-bisphosphate

中文翻译：

---

低葡萄糖通过抑制糖酵解和通过上调 miR-210-5p 诱导能量应激来增强二甲双胍对胰腺癌细胞的抑制作用。

探讨不同葡萄糖条件下二甲双胍对胰腺癌细胞PANC-1抗肿瘤作用差异的机制。我们在 25 mM 和 5 mM 葡萄糖培养基中培养 PANC-1 细胞，然后用或不用二甲双胍处理。结果表明二甲双胍显着抑制增殖和活力，诱导PANC-1细胞凋亡，低糖组比高糖组更明显。二甲双胍在低糖中上调 miR-210-5p 的表达，但在高糖中不上调。miR-210-5p 模拟物抑制 PANC-1 细胞的活力并进一步增强二甲双胍的抑制作用。miR-210-5p 下调 PFKFB2（miR-210-5p 的预测靶基因）的表达，降低 PFK1 和 LDH 的活性。二甲双胍显着抑制低糖组磷酸化-PFKFB2(p-PFKFB2)的表达，抑制低糖组和高糖组的LDH活性，从而抑制无氧糖酵解，诱导能量应激。高糖组细胞可以通过增加葡萄糖消耗对二甲双胍诱导的能量应激进行补偿性适应。然而，由于低糖组细胞的葡萄糖供应有限且对无氧糖酵解的高度依赖，它们无法进行有效的适应性补偿。因此，低糖组的细胞更容易受到二甲双胍的毒性作用。综上所述，二甲双胍对低糖培养的PANC-1细胞抑制作用增强可能是由于miR-210-5p表达上调，

缩写

PC：胰腺癌；DM：糖尿病；PFKFB2：6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶2；PFK1：磷酸果糖激酶；LDH：乳酸脱氢酶；F-2,6-BP：果糖 2,6-二磷酸