PDF(Pubmed)
Abstract：
Mutations in p53 and KRAS are seen in most cases of colon cancer. The impact of these mutations on signaling pathways related to cancer growth has been studied in depth, but relatively less is known on their effects on amino acid transporters in cancer cells. This represents a significant knowledge gap because amino acid nutrition in cancer cells profoundly influences macropinocytosis and ferroptosis, two processes with opposing effects on tumor growth. Here, we used isogenic colon cancer cell lines to investigate the effects of p53 deletion and KRAS activation on two amino acid transporters relevant to macropinocytosis (SLC38A5) and ferroptosis (SLC7A11). Our studies show that the predominant effect of p53 deletion is to induce SLC7A11 with the resultant potentiation of antioxidant machinery and protection of cancer cells from ferroptosis, whereas KRAS activation induces not only SLC7A11 but also SLC38A5, thus offering protection from ferroptosis as well as improving amino acid nutrition in cancer cells via accelerated macropinocytosis. Niclosamide, an FDA-approved anti-helminthic, blocks the functions of SLC7A11 and SLC38A5, thus inducing ferroptosis and suppressing macropinocytosis, with the resultant effective reversal of tumor-promoting actions of oncogenic changes in p53 and KRAS. These findings underscore the potential of this drug in colon cancer treatment.
摘要：
p53和KRAS的突变见于大多数结肠癌病例。这些突变对与癌症生长相关的信号通路的影响已经被深入研究,但是对它们对癌细胞中氨基酸转运蛋白的影响的了解相对较少。这代表了一个重大的知识差距，因为癌细胞中的氨基酸营养会深刻地影响巨细胞胞吞作用和铁细胞凋亡，对肿瘤生长有相反影响的两个过程。这里,我们使用等基因结肠癌细胞系来研究p53缺失和KRAS激活对两个与巨噬细胞增多(SLC38A5)和铁凋亡(SLC7A11)相关的氨基酸转运蛋白的影响。我们的研究表明，p53缺失的主要作用是诱导SLC7A11，从而增强抗氧化机制并保护癌细胞免受铁凋亡，而KRAS激活不仅诱导SLC7A11，而且诱导SLC38A5，从而提供对铁凋亡的保护，并通过加速巨细胞胞吞作用改善癌细胞中的氨基酸营养。氯硝柳胺,FDA批准的抗蠕虫药，阻断SLC7A11和SLC38A5的功能，从而诱导铁细胞凋亡并抑制巨噬细胞增多，从而有效逆转p53和KRAS中致癌变化的肿瘤促进作用。这些发现强调了这种药物在结肠癌治疗中的潜力。
