六价铬,Cr(VI),是已知的致癌物和环境健康问题。已经确定活性氧,基因组不稳定性,和DNA损伤修复缺陷是Cr(VI)诱导的致癌机制的重要因素。然而,关于Cr(VI)诱导致癌作用的机制,一些癌症的标志仍未得到充分研究。脂肪生成的增加对多种类型癌症的癌变和肿瘤发生很重要,然而,脂肪生成增加在Cr(VI)癌变中的作用尚不清楚。我们在这里报道了Cr(VI)诱导的三种人肺细胞系(BEAS-2B,BEP2D,和WTHBF-6)导致脂肪生成增加(棕榈酸水平),和Cr(VI)转化的细胞表达增加了关键的脂肪生成蛋白(ATP柠檬酸裂解酶[ACLY],乙酰辅酶A羧化酶[ACC1],和脂肪酸合成酶[FASN])。我们还确定,与它们的传代匹配的对照细胞相比,Cr(VI)转化的细胞没有表现出脂肪酸氧化或脂滴的增加。此外,我们观察到ACLY的增加,与正常相邻肺组织相比,肺肿瘤组织中的ACC1和FASN(在铬酸盐工人中死于铬酸盐诱导的肿瘤)。接下来,使用已知的FASN抑制剂(C75),我们用这种抑制剂处理Cr(VI)转化的BEAS-2B,并测量细胞生长,FASN蛋白表达,在软琼脂中生长。我们观察到FASN抑制导致蛋白质表达降低,细胞生长减少,和抑制软琼脂中的菌落生长。接下来,使用shRNA敲低Cr(VI)转化的BEAS-2B细胞中的FASN蛋白,我们发现Cr(VI)转化的BEAS-2B细胞的FASN蛋白表达减少和异种移植肿瘤发展丧失。这些结果证明FASN对于Cr(VI)转化的细胞生长和癌症性质是重要的。总之,这些数据表明,Cr(VI)-转化在体外引起脂肪生成的增加,并且这种增加对于Cr(VI)转化的细胞是至关重要的。
Hexavalent chromium, Cr(VI), is a known carcinogen and environmental health concern. It has been established that reactive oxygen species, genomic instability, and DNA damage repair deficiency are important contributors to the Cr(VI)-induced carcinogenesis mechanism. However, some hallmarks of cancer remain under-researched regarding the mechanism behind Cr(VI)-induced carcinogenesis. Increased lipogenesis is important to carcinogenesis and tumorigenesis in multiple types of cancers, yet the role increased lipogenesis has in Cr(VI) carcinogenesis is unclear. We report here that Cr(VI)-induced transformation of three human lung cell lines (BEAS-2B, BEP2D, and WTHBF-6) resulted in increased lipogenesis (palmitic acid levels), and Cr(VI)-transformed cells had an increased expression of key lipogenesis proteins (ATP citrate lyase [ACLY], acetyl-CoA carboxylase [ACC1], and fatty acid synthase [FASN]). We also determined that the Cr(VI)-transformed cells did not exhibit an increase in fatty acid oxidation or lipid droplets compared to their passage-matched control cells. Additionally, we observed increases in ACLY, ACC1, and FASN in lung tumor tissue compared with normal-adjacent lung tissue (in chromate workers that died of chromate-induced tumors). Next, using a known FASN inhibitor (C75), we treated Cr(VI)-transformed BEAS-2B with this inhibitor and measured cell growth, FASN protein expression, and growth in soft agar. We observed that FASN inhibition results in a decreased protein expression, decreased cell growth, and the inhibition of colony growth in soft agar. Next, using shRNA to knock down the FASN protein in Cr(VI)-transformed BEAS-2B cells, we saw a decrease in FASN protein expression and a loss of the xenograft tumor development of Cr(VI)-transformed BEAS-2B cells. These results demonstrate that FASN is important for Cr(VI)-transformed cell growth and cancer properties. In conclusion, these data show that Cr(VI)-transformation in vitro caused an increase in lipogenesis, and that this increase is vital for Cr(VI)-transformed cells.