The study of the respiratory activities of prostate cancer DU145 cells under acidic pH
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Keywords:
prostate cancer, mitochondria respiration, oxidative phosphorylation, acidic tumor microenvironment, succinate.Abstract
Acidic pH is toxic to many cells, including tumors. However, if tumors have successfully adapted to their condition, and use it for their own cellular activation, thisincreases drug resistance and leads to more aggressive behavior. Therefore, management of tumor pH and inhibitionof blockade of proton-sensing system are importantin not only raising drug efficacy, e.g. mitoxantrone, but inpreventing metastasis. Recent advances in cancer research have revealed a significant contribution of the tumorigenic microenvironment to metabolic reprogramming of tumors. Prostate cancer cells rearrange their metabolism, so that they support their elevated oxidative phosphorylation and promote a cancer friendly tumor microenvironment. This work aimed to study the respiratory activities of prostate cancer DU145 cells under acidic pH mimicking the tumorigenic microenvironment condition. The respiratory and oxidative phosphorylation abilities of prostate cancer DU145 and other cells were studied by high-resolution respirometry. An important finding was that prostate cancer cells in an environment at pH 6.8 are capable of consuming TCA cycle intermediates, such as succinate, citrate and others, available in extracellular fluids, while physiological pH 7.4 was not favorable for this process. This process could yield novel targets for anti-cancer therapy and has the potential to be used for imaging-based diagnostics to identify non-glycolytic tumors.References
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3Lamonte G., et al. Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress // Cancer Metab. – 2013. – Vol.1. – №1. – P. 23.
4Riemann A., et al. Acidic environment leads to ROS-induced MAPK signaling in cancer cells // PLoS One. – 2011. – Vol. 6. – №7. – P. e22445.
5 Martinez-Outschoorn U.E., SotgiaF., LisantiM.P. Power surge: supporting cells "fuel" cancer cell mitochondria // Cell Metab. – 2012. – Vol. 15. – №1. – P. 4-5.
6 Whitaker-Menezes D., et al. Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue // Cell Cycle. – 2011. – Vol.10. – №23. – P. 4047-4064.
7 Hems R.,. StubbsM.,. KrebsH.A. Restricted permeability of rat liver for glutamate and succinate // Biochem J. – 1968. – Vol. 107. – №6. – P. 807-815.
8 Clerc P., PolsterB.M. Investigation of mitochondrial dysfunction by sequential microplate-based respiration measurements from intact and permeabilized neurons // PLoS One. – 2012. – Vol. 7. – №4. – P. e34465.
9 Spencer T.L. The transport and oxidation of succinate by Ehrlich ascites-tumour cells // Biochem J. – 1976. – Vol. 160. – №1. – P. 121-123.
10 Guder W.G., Wirthensohn G. Renal turnover of substrates. In Renal Transport of Organic Substances. – Berlin:Springer-Verlag, 1981. – P.66-77
11 Sadagopan N., et al. Circulating succinate is elevated in rodent models of hypertension and metabolic disease // Am J Hypertens. – 2007. – Vol. 20. – №11. – P.1209-1215.
12Hems D.A., BrosnanJ.T. Effects of ischaemia on content of metabolites in rat liver and kidney in vivo // Biochem J. – 1970. – Vol. 120. – №1. – P.105-111.
13 Gibala M.J., et al. Tricarboxylic acid cycle intermediate pool size and estimated cycle flux in human muscle during exercise // Am J Physiol. – 1998. – Vol. 275. – №2 (1). – P.235-242.
14 Lewis G.D., et al. Metabolic signatures of exercise in human plasma // Sci Transl Med. – 2010. – Vol. 2. – №33. – P. 33-37.
15 Brennan J.P., et al. FCCP is cardioprotective at concentrations that cause mitochondrial oxidation without detectable depolarisation // Cardiovasc Res. – 2006. – Vol. 72. – №2. – P. 322-330.
16 Lan A., Lagadic-Gossmann D., Lemaire C., Brenner C., Jan G. Acidicextracellular pH shifts colorectal cancer cell death from apoptosis tonecrosis upon exposure to propionate and acetate, major end-productsof the human probiotic propionibacteria // Apoptosis. – 2007, – Vol. 12. –№3. – P. 573–591.
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Zhunussova, A. S., Orynbayeva, Z. S., & Tuleukhanov, S. T. (2016). The study of the respiratory activities of prostate cancer DU145 cells under acidic pH. Experimental Biology, 65(3), 306–312. Retrieved from https://bb.kaznu.kz/index.php/biology/article/view/1132
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HUMAN AND ANIMAL PHYSIOLOGY
