Schointuch Monica N, Gilliam Timothy P, Stine Jessica E, Han Xiaoyun, Zhou Chunxiao, Gehrig Paola A, Kim Kenneth, Bae-Jump Victoria L
Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.
ShanDong Tumor Hospital, Jinan University, Division of Gynecologic Oncology, Jinan 250117, PR China.
Gynecol Oncol. 2014 Aug;134(2):346-55. doi: 10.1016/j.ygyno.2014.05.015. Epub 2014 May 28.
Our goal was to evaluate the effects of simvastatin on endometrial cancer cell lines and primary cultures of endometrial cancer cells.
Cell proliferation in the ECC-1 and Ishikawa endometrial cancer cell lines and primary cultures of endometrial cancer cells was assessed by MTT assay. Apoptosis and cell cycle were detected by Annexin V assay and propidium iodide staining, respectively. Reactive oxygen species and cell adhesion were assessed using ELISA assays. Invasion was analyzed using a transwell invasion assay. Mitochondrial DNA damage was confirmed using qPCR. The effects of simvastatin on the AKT/mTOR and MAPK pathways were determined by Western blotting.
Simvastatin inhibited cell proliferation in a dose-dependent manner in both endometrial cancer cell lines and 5/8 primary cultures of endometrial cancer cells. Simvastatin treatment resulted in G1 cell cycle arrest, a reduction in the enzymatic activity of HMG-CoA, induction of apoptosis as well as DNA damage and cellular stress. Treatment with simvastatin resulted in inhibition of the MAPK pathway and exhibited differential effects on the AKT/mTOR pathway in the ECC-1 and Ishikawa cells. Minimal change in AKT phosphorylation was seen in both cell lines. An increase in phosphorylated S6 was seen in ECC-1 and a decrease was seen in Ishikawa. Treatment with simvastatin reduced cell adhesion and invasion (p<0.01) in both cell lines.
Simvastatin had significant anti-proliferative and anti-metastatic effects in endometrial cancer cells, possibly through modulation of the MAPK and AKT/mTOR pathways, suggesting that statins may be a promising treatment strategy for endometrial cancer.
我们的目标是评估辛伐他汀对子宫内膜癌细胞系和子宫内膜癌原代培养细胞的影响。
采用MTT法评估ECC-1和 Ishikawa子宫内膜癌细胞系以及子宫内膜癌原代培养细胞的细胞增殖情况。分别通过膜联蛋白V法和碘化丙啶染色检测细胞凋亡和细胞周期。使用酶联免疫吸附测定法评估活性氧和细胞黏附情况。采用Transwell侵袭试验分析侵袭情况。使用定量聚合酶链反应确认线粒体DNA损伤。通过蛋白质印迹法确定辛伐他汀对AKT/mTOR和MAPK信号通路的影响。
辛伐他汀在子宫内膜癌细胞系和5/8的子宫内膜癌原代培养细胞中均以剂量依赖性方式抑制细胞增殖。辛伐他汀处理导致G1期细胞周期停滞、HMG-CoA酶活性降低、诱导细胞凋亡以及DNA损伤和细胞应激。辛伐他汀处理导致MAPK信号通路受到抑制，并且在ECC-1和Ishikawa细胞中对AKT/mTOR信号通路表现出不同的影响。在两种细胞系中均观察到AKT磷酸化变化极小。在ECC-1中观察到磷酸化S6增加，而在Ishikawa中观察到减少。辛伐他汀处理降低了两种细胞系中的细胞黏附和侵袭能力（p<0.01）。
辛伐他汀在子宫内膜癌细胞中具有显著的抗增殖和抗转移作用，可能是通过调节MAPK和AKT/mTOR信号通路实现的，这表明他汀类药物可能是一种有前景的子宫内膜癌治疗策略。
