Feng Shuitu, Zheng Zhigao, Feng Lihua, Yang Lihong, Chen Zuhong, Lin Yubiao, Gao Yingqin, Chen Yide
Department of Medical Oncology, Xiamen Haicang Hospital, Xiamen, Fujian 361026, P.R. China.
Internal Medicine Department, Xiamen Navy Hospital, Xiamen, Fujian 361000, P.R. China.
Oncol Rep. 2016 Dec;36(6):3207-3214. doi: 10.3892/or.2016.5154. Epub 2016 Oct 7.
The cancer stem cell (CSC) model suggests that a small subset of cancer cells possess stem cell properties and plays a crucial role in tumor initiation, metastasis and resistance to anticancer therapy. Exploration of the specific therapies targeting at CSCs has been a crucial issue in antitumor research. Gastric cancer (GC) cells often exist in an ischemic microenvironment with acidic conditions in vivo, thus maintenance of cellular pH homeostasis is important for the survival and function of GC cells. Proton pump inhibitors (PPIs) may prevent intracellular proton extrusions which consequently reduce cancer cell survival under acidic conditions. The effects of PPIs on the suppression of the viability and invasiveness of GC cells have been reported, but the functional role of pantoprazole (PPZ) in GC cells remains unknown. In this study, we found that when cells were treated with PPZ, the 5‑fluorouracil (5‑FU) chemosensitivity was upregulated, meanwhile the sphere formation ability and the relative expression levels of stem cell markers CD44, CD24, ABCG2, EpCAM and Lgr5 were significantly decreased. It was hypothesized that PPZ inhibits the GC CSCs. Successively a sphere formation culture was performed to establish CSC models and the effect of PPZ on GC CSCs from SGC-7901 and HGC‑27 cells was explored. The addition of PPZ reduced the relative expression of CSC markers and anti‑drug markers accompanied by a decrease in proliferation, 5‑FU chemoresistance and self‑renewal capacity via epithelial‑mesenchymal transition (EMT)/β‑catenin pathways. The study suggests that PPZ could be a promising novel specific therapeutic strategy for targeting GC CSCs.
癌症干细胞（CSC）模型表明，一小部分癌细胞具有干细胞特性，在肿瘤起始、转移及抗癌治疗耐药性方面发挥关键作用。探索针对CSC的特异性疗法一直是抗肿瘤研究中的关键问题。胃癌（GC）细胞在体内常存在于伴有酸性条件的缺血微环境中，因此维持细胞内pH稳态对GC细胞的存活和功能很重要。质子泵抑制剂（PPI）可能会阻止细胞内质子外流，从而降低酸性条件下癌细胞的存活率。已有报道称PPI对抑制GC细胞活力和侵袭性有作用，但泮托拉唑（PPZ）在GC细胞中的功能作用尚不清楚。在本研究中，我们发现当用PPZ处理细胞时，5-氟尿嘧啶（5-FU）的化疗敏感性上调，同时成球能力以及干细胞标志物CD44、CD24、ABCG2、EpCAM和Lgr5的相对表达水平显著降低。据推测，PPZ可抑制GC CSC。随后进行了成球培养以建立CSC模型，并探索了PPZ对SGC-7901和HGC-27细胞来源的GC CSC的作用。添加PPZ可降低CSC标志物和抗药标志物的相对表达，同时通过上皮-间质转化（EMT）/β-连环蛋白途径降低增殖、5-FU化疗耐药性和自我更新能力。该研究表明，PPZ可能是一种有前景的针对GC CSC的新型特异性治疗策略。
