Proton Pump Inhibition Enhances the Cytotoxicity of Paclitaxel in Cervical Cancer.
- Author:
Taejong SONG
1
;
Hye Kyung JEON
;
Ji Eun HONG
;
Jung Joo CHOI
;
Tae Joong KIM
;
Chel Hun CHOI
;
Duk Soo BAE
;
Byoung Gie KIM
;
Jeong Won LEE
Author Information
- Publication Type:Original Article
- Keywords: Uterine cervical neoplasms; Vacuolar proton-translocating ATPases; Proton pump inhibitors; Esomeprazole; Small interfering RNA; Antineoplastic agents
- MeSH: Adenocarcinoma; Adenosine Triphosphatases; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line; Cell Proliferation; Disease-Free Survival; Enzyme-Linked Immunosorbent Assay; Esomeprazole; Humans; Immunohistochemistry; Paclitaxel*; Prognosis; Proton Pump Inhibitors; Proton Pumps*; Protons*; Risk Factors; RNA, Small Interfering; Transfection; Uterine Cervical Neoplasms*; Vacuolar Proton-Translocating ATPases
- From:Cancer Research and Treatment 2017;49(3):595-606
- CountryRepublic of Korea
- Language:English
- Abstract: PURPOSE: This study was conducted to investigate whether a proton pump inhibitor (PPI) could enhance chemosensitivity via the inhibition of vacuolar-type H⁺ ATPase (V-ATPase) in cervical cancer. MATERIALS AND METHODS: The expression of V-ATPase was evaluated in 351 formalin-fixed, paraffin-embedded human cervical cancer tissues using immunohistochemistry and compared with clinicopathologic risk factors for disease prognosis. The influence of cell proliferation and apoptosis following V-ATPase siRNA transfection or esomeprazole pretreatment was assessed in cervical cancer cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and enzyme-linked immunosorbent assay, respectively. RESULTS: Immunohistochemical analysis revealed that V-ATPase was expressed in about 60% of cervical cancer tissue samples (211/351), and the expression was predominantly found in adenocarcinoma histology (p=0.016). Among patients with initially bulky cervical cancer (n=89), those with V-ATPase expression had shorter disease-free survival (p=0.005) and overall survival (p=0.023). Co-treatment with V-ATPase siRNA or esomeprazole with paclitaxel significantly decreased the cell proliferation of cervical cancer cell lines, including HeLa and INT407, compared to cell lines treated with paclitaxel alone (p < 0.01). Moreover, V-ATPase siRNA or esomeprazole followed by paclitaxel significantly increased the expression of active caspase-3 in these cells compared to cells treated with paclitaxel alone (both, p < 0.05). CONCLUSION: V-ATPase was predominantly expressed in cervical adenocarcinoma, and the expression of V-ATPases was associated with poor prognosis. The inhibition of V-ATPase via siRNA or PPI (esomeprazole) might enhance the chemosensitivity of paclitaxel in cervical cancer cells.
