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Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH

机译:维生素C通过靶向GapDH选择性地杀死KRas和BRaF突变体结肠直肠癌细胞

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摘要

More than half of human colorectal cancers (CRCs) carry either KRAS or BRAF mutations, and are often refractory to approved targeted therapies. We report that cultured CRC cells harboring KRAS or BRAF mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, ROS accumulates and inactivates glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibiting GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wild-type cells. High-dose vitamin C impaired tumor growth in Apc/KrasG12D mutant mice. These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations.
机译:超过一半的人结肠直肠癌(CRCS)携带KRAS或BRAF突变,并且通常难以批准靶向疗法。我们报告说,当暴露于高水平的维生素C时,选择性地杀死含有KRA或BRAF突变的培养的CRC细胞。这种效果是由于通过Glut1葡萄糖转运蛋白增加了氧化形式的维生素C,脱氢血酸盐(DHA)的摄取。随着细胞内DHA降至维生素C,耗尽谷胱甘肽,增加DHA摄取会导致氧化应激。因此,ROS累积和灭活甘油醛3-磷酸脱氢酶(GAPDH)。抑制高糖浆KRAS或BRAF突变细胞中的GAPDH导致在KRAS和BRAF野生型细胞中未见的能量危机和细胞死亡。高剂量维生素C在APC / KRASG12D突变小鼠中肿瘤生长受损。这些结果提供了一种机械理由,用于探索维生素C与KRAS或BRAF突变的CRCS的治疗用途。

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