|
对于雌激素受体阳性乳腺癌，既往研究发现缺氧诱导因子（HIF）-1α可使内分泌治疗耐药，而唑来膦酸可以减少HIF-1α表达。 2018年1月29日，希腊《分子医学报告》在线发表复旦大学附属肿瘤医院和上海医学院贾晓青、程竞仪、沈镇宙、邵志敏、柳光宇的研究报告，调查了唑来膦酸＋氟维司群抑制HIF-1α的可能机制。 该研究首先利用体外持续表达HIF-1α的MCF-7乳腺癌细胞，通过蛋白质印迹法，检测细胞增殖、克隆能力和HIF-1α表达。随后，利用HIF-1α过表达的MCF-7乳腺癌细胞，建立小鼠异种移植模型，分别使用磷酸盐缓冲生理盐水、氟维司群、唑来膦酸、氟维司群＋唑来膦酸进行处理。对肿瘤大小进行比较，并利用动物18F-氟米索硝唑（FMISO）正电子发射计算机断层扫描（PET-CT）检测异种移植肿瘤缺氧状况。通过免疫组织化学和蛋白质印迹法，检测异种移植肿瘤HIF-1α蛋白质表达水平。 结果发现，HIF-1α过表达的异种移植肿瘤与对照肿瘤相比，生长较快较大。动物18F-FMISO/PET-CT也证实了这些结果，HIF-1α过表达的异种移植肿瘤与对照肿瘤相比，18F-FMISO摄取率显著较高。此外，唑来膦酸＋氟维司群协同作用显著减少小鼠体内异种移植模型肿瘤负荷。同样，唑来膦酸＋氟维司群显著减少体外肿瘤细胞生长。而且，单用唑来膦酸，无法抑制持续表达HIF-1α的MCF-7肿瘤细胞生长。并且，唑来膦酸显著抑制细胞外信号调节蛋白激酶（ERK）1/2磷酸化，而磷脂酰肌醇-3-羟激酶（PI3K）与AKT信号传导不受影响。 因此，该研究表明，唑来膦酸通过抑制ERK/HIF-1α通路，显著增加乳腺癌细胞对氟维司群的敏感性。 相关阅读 Mol Med Rep. 2018 Jan 29. [Epub ahead of print] Zoledronic acid sensitizes breast cancer cells to fulvestrant via ERK/HIF-1 pathway inhibition in vivo. Jia X, Cheng J, Shen Z, Shao Z, Liu G. Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China. Previous studies have reported that hypoxia-inducible factor (HIF)-1α confers endocrine resistance and that zoledronic acid (ZOL) decreases HIF-1α expression in estrogen receptor-positive breast cancer. The present study investigated the effect of the combination treatment with ZOL and fulvestrant and its possible mechanism for HIF-1α inhibition in vitro and in vivo. First, cell proliferation, clonogenic ability and HIF-1α expression by western blotting were determined in MCF-7 breast cancer cells stably expressing HIF-1α in vitro. Next, a mouse xenograft model was established with the HIF-1α-overexpressing MCF-7 breast cancer cells, and treated with PBS, fulvestrant, ZOL or fulvestrant plus ZOL. Tumor volumes were compared and animal [18F]-fluoromisonidazole (FMISO) positron emission tomography-computer tomography (PET-CT) was used to detect the hypoxic status of the xenograft tumors. Protein expression levels of HIF-1α in the xenograft tumors were detected by immunohistochemistry and western blotting. The results demonstrated that the HIF-1α-overexpressing xenograft tumors grew faster and larger compared with control tumors. The animal [18F]-FMISO PET-CT also confirmed these results. [18F]-FMISO uptake was significantly higher in HIF-1α-overexpressing xenograft tumors compared with control tumors. In addition, the combination treatment with ZOL and fulvestrant acted synergistically in the mouse xenograft model in vivo to significantly reduce tumor burden. Similarly, combination of ZOL and fulvestrant significantly reduced tumor cell growth in vitro. ZOL alone did not inhibit the tumor growth of MCF-7 cells stably expressing HIF-1α. Furthermore, ZOL significantly inhibited extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, while phosphoinositide 3-kinase/AKT signaling was not affected. In conclusion, the present study demonstrated that ZOL significantly increased the sensitivity of breast cancer cells to fulvestrant through inhibition of the ERK/HIF-1α pathway. PMID: 29393454 DOI: 10.3892/mmr.2018.8514 |
|
|
