Proton Pump Inhibition Enhances the Cytotoxicity of Paclitaxel in Cervical Cancer.
OBJECTIVE
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.


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).


CONCLUSIONS
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.
Department of Obstetrics and Gynecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
Taejong
T
Song
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Hye-Kyung
HK
Jeon
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Ji Eun
JE
Hong
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Jung-Joo
JJ
Choi
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Tae-Joong
TJ
Kim
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Chel Hun
CH
Choi
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Duk-Soo
DS
Bae
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Byoung-Gie
BG
Kim
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Jeong-Won
JW
Lee
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004357:Drug Synergism; D064098:Esomeprazole / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D054328:Proton Pump Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017494:Proton Pumps / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D054328:Proton Pump Inhibitors; D017494:Proton Pumps; D034741:RNA, Small Interfering; D025262:Vacuolar Proton-Translocating ATPases; D064098:Esomeprazole; D017239:Paclitaxel
Antineoplastic agents; Esomeprazole; Proton pump inhibitors; Small interfering RNA; Uterine cervical neoplasms; Vacuolar proton-translocating ATPases
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