Evaluation of the role of pH in cancer cell proliferation
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1
University of Nottingham, Obstetritics and Gynaecology, United Kingdom
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2
Manipal University, Pharmacology and Theraprutics, India
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3
University of Nottingham, Faculty of Medicine and Health Sciences, United Kingdom
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4
University of Nottingham, Faculty of Medicine and Health Sciences, United Kingdom
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5
University of Nottingham, Division of Surgery, United Kingdom
Background and aim. A common feature of tumours is a shift in cellular metabolism generating a high extracellular acidosis. In addition hypoxia contributes to the exacerbation of tumour extracellular acidosis. The potential toxic effects of low extracellular pH (pHe) are counteracted by cellular mechanisms including potassium channels and the H+/K+ ATPase proton pump. We hypothesize that regulation of pH of the tumour microenvironment affects cancer cell proliferation through pH sensitive membrane proteins. The present study was aimed at investigating and comparing the effect of pH and cellular pH regulating mechanisms on proliferation of the ovarian cancer (SKOV3) and osteosarcoma (MG63) cell lines.
Methods. The SKOV3 and MG63 cell lines were cultured in media of pHe ranging from 6.0-6.3 to 7.5 to compare their response to alterations in pHe in both hypoxia (20% CO2, 3% O2) and normoxia (5% CO2, 95% air). Cell proliferation assays were performed in the presence and absence of drugs known to inhibit the H+/K+ ATPase proton pump (omeprazole), EAG channel (E-4031) and the pH-sensitive potassium channel, TASK3 (methanandamide) over 24 and 72 hour time-points using MTS cell proliferation assay. Immunofluorescence and Western blotting techniques were used to detect the presence of TASK3 channels in SKOV3 cells cultured in pHe 6.3. Data was compared using one-way ANOVA. All experiments were repeated thrice.
Results. The SKOV3 and MG63 cells showed an increased rate of proliferation after culturing for 72 hours in pH 6.3-6.0 compared with pH 7.5 (p< 0.05).E -4031 and methanandamide at 0.1 μM decreased cell proliferation significantly in SKOV3 and MG63 cells after 72 hours in pHe 6.3-6.0 in comparison to pHe 7.5 (p< 0.05). Omeprazole at 10 μg/ml significantly decreased cell proliferation of MG63 cells within 24 hours at a pHe of 6.3 in comparison to pHe 7.5 (p< 0.05). The TASK3 channels were observed in SKOV3 cells at pHe 6.3 through immunofluorescence and were confirmed by Western blotting.
Conclusions / Discussion. Inhibitors of potassium channels and proton pumps elicited a variable response from proliferation experiments with MG63 and SKOV3 cell lines. A change in pHe influenced proliferation, indicating dependence on cellular pH regulating systems and membrane protein. The presence of these pH regulating systems often works in correlation with change in cellular metabolism owing to altered intracellular pH and pHe. Further investigation is required to understand the fundamentals of pH regulatory systems to meet the challenge of targeting tumour metabolism and acidosis as an anti-cancer therapy.
Acknowledgements
The technical, academic and financial support of The University of Nottingham, UK and Manipal University, India is highly acknowledged
References
1. Asher V, Warren AY,, Shaw RW, Sowter H, Bali A, Khan RN (2011) The role of EAG and HERG channels in cell proliferation and apoptotic cell death in SK-OV-3 ovarian cancer cell line. Cancer Cell International 11:6.
2. Innamaa A, Jackson L, Asher V, Van Shalkwyk G, Warren AY, Hay D, Bali A, Sowter H, Khan R (2013) Expression and Prognostic Significance of the Oncogenic K2P Potassium Channel KCNK9 (TASK-3) in Ovarian Carcinoma. Anticancer Res 33: 1401-8.
Keywords:
potassium channel inhibitor,
TASK3 Channel,
ovarian cancer,
Proton Pump Inhibitors,
alteration in pHe
Conference:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer, Garching, Germany, 10 Oct - 12 Oct, 2013.
Presentation Type:
Abstract
Topic:
4. pH and energy metabolism
Citation:
Bose
U,
Rauch
C,
Allegrucci
C,
Tufarelli
C and
Khan
RN
(2014). Evaluation of the role of pH in cancer cell proliferation.
Front. Pharmacol.
Conference Abstract:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer.
doi: 10.3389/conf.fphar.2014.61.00009
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Received:
29 Jan 2014;
Published Online:
07 Feb 2014.
*
Correspondence:
Mr. Ujjal Bose, University of Nottingham, Obstetritics and Gynaecology, Derby, Derbyshire, DE22 3DT, United Kingdom, bose.ujjal@gmail.com