Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells (Retracted article. See vol. 40, 2019)
Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells (Retracted article. See vol. 40, 2019)
复制标题
DOI：
10.1093/carcin/bgu124
复制
发表时间：
2014-10-01
期刊：
影响因子：
4.7
通讯作者：
Chen, Ching-Shih
中科院分区：
文献类型：
--
作者：
Lai, I-Lu;Chou, Chih-Chien;Chen, Ching-Shih
吉西他滨耐药仍然是一个重大的临床挑战。在这里，我们使用了一种新型的葡萄糖转运蛋白(GLUT)抑制剂CG-5作为概念验证化合物来研究靶向Warburg效应来克服胰腺癌吉西他滨耐药的治疗作用。观察吉西他滨和/或CG-5对吉西他滨敏感和耐药胰腺癌细胞的存活率、存活率、葡萄糖摄取和DNA损伤的影响。为确定吉西他滨耐药的分子基础和CG-5诱导吉西他滨增敏的机制，进行了机理研究。在吉西他滨耐药的胰腺癌移植瘤模型上，研究了CG-5对吉西他滨敏感性的影响。与吉西他滨敏感的胰腺癌细胞相比，耐药的PANC-1和PANC-1(GemR)细胞对吉西他滨的反应是通过E2F1介导的转录激活增加核糖核苷酸还原酶M2催化亚单位(RRM2)的表达。作为一种泛GLUT抑制剂，CG-5通过减少E2F1的表达来阻断吉西他滨诱导的RRM2的上调，从而加强吉西他滨诱导的DNA损伤和对细胞存活的抑制。CG-5对E2F1表达的抑制是通过诱导以前未报道的E2F1靶向microRNA miR-520F介导的。口服CG-5与吉西他滨治疗相比，在体内对Panc-1(GemR)异种移植瘤生长的抑制作用比单独使用任何一种药物都要大。Glut抑制可能是增强吉西他滨治疗胰腺癌活性的有效策略。
Gemcitabine resistance remains a significant clinical challenge. Here, we used a novel glucose transporter (Glut) inhibitor, CG-5, as a proof-of-concept compound to investigate the therapeutic utility of targeting the Warburg effect to overcome gemcitabine resistance in pancreatic cancer. The effects of gemcitabine and/or CG-5 on viability, survival, glucose uptake and DNA damage were evaluated in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cell lines. Mechanistic studies were conducted to determine the molecular basis of gemcitabine resistance and the mechanism of CG-5-induced sensitization to gemcitabine. The effects of CG-5 on gemcitabine sensitivity were investigated in a xenograft tumor model of gemcitabine-resistant pancreatic cancer. In contrast to gemcitabine-sensitive pancreatic cancer cells, the resistant Panc-1 and Panc-1(GemR) cells responded to gemcitabine by increasing the expression of ribonucleotide reductase M2 catalytic subunit (RRM2) through E2F1-mediated transcriptional activation. Acting as a pan-Glut inhibitor, CG-5 abrogated this gemcitabine-induced upregulation of RRM2 through decreased E2F1 expression, thereby enhancing gemcitabine-induced DNA damage and inhibition of cell survival. This CG-5-induced inhibition of E2F1 expression was mediated by the induction of a previously unreported E2F1-targeted microRNA, miR-520f. The addition of oral CG-5 to gemcitabine therapy caused greater suppression of Panc-1(GemR) xenograft tumor growth in vivo than either drug alone. Glut inhibition may be an effective strategy to enhance gemcitabine activity for the treatment of pancreatic cancer.