Duan Jiangman, Chen Lishan, Zhou Minyu, Zhang Jingwen, Sun Li, Huang Na, Bin Jianping, Liao Yulin, Liao Wangjun
Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, P.R. China.
Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, P.R. China.
Oncol Rep. 2017 May;37(5):2583-2592. doi: 10.3892/or.2017.5519. Epub 2017 Mar 22.
The effect of chemotherapeutic agents is limited as a result of drug resistance, which demands prompt solutions provided by clinical studies. To date, the underlying mechanisms of chemotherapy resistance are relatively unknown. Metastasis-associated in colon cancer 1 (MACC1) is an oncogene associated with the progression and prognosis of gastric cancer (GC). Bioinformatic analysis revealed that MACC1 is positively associated with fatty acid synthase (FASN), a major enzyme of lipogenesis, and drives chemoresistance to oxaliplatin in GC. Similar findings were demonstrated in two GC cell lines (BGC-823 and MKN-28) with MACC1 ectopic expression. We next employed FASN inhibitor C75 or siFASN (small interfering RNA targeted to FASN) to block endogenous fatty acid metabolism and it was revealed that cell proliferation and chemoresistance to oxaliplatin induced by MACC1 upregulation were attenuated by FASN blockade to various extents. Conclusively, these outcomes highlight a novel role of MACC1 in GC cell lipogenesis, and suggest that MACC1 may be an attractive target to decrease oxaliplatin resistance in GC.
由于耐药性，化疗药物的效果有限，这需要临床研究提供及时的解决方案。迄今为止，化疗耐药的潜在机制相对尚不明确。结肠癌转移相关蛋白1（MACC1）是一种与胃癌（GC）进展和预后相关的癌基因。生物信息学分析显示，MACC1与脂肪酸合酶（FASN，脂肪生成的主要酶）呈正相关，并驱动GC对奥沙利铂的化疗耐药。在两个具有MACC1异位表达的GC细胞系（BGC - 823和MKN - 28）中也证实了类似的发现。接下来，我们使用FASN抑制剂C75或siFASN（靶向FASN的小干扰RNA）来阻断内源性脂肪酸代谢，结果显示，FASN阻断在不同程度上减弱了MACC1上调诱导的细胞增殖和对奥沙利铂的化疗耐药。总之，这些结果突出了MACC1在GC细胞脂肪生成中的新作用，并表明MACC1可能是降低GC中奥沙利铂耐药性的一个有吸引力的靶点。
