Mitochondria sustain store-operated currents in colon cancer cells but not in normal colonic cells: reversal by non-steroidal anti-inflammatory drugs
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Miriam Hernández-Morales1, Diego Sobradillo1, Ruth A. Valero1, Eva Muñoz1, Daniel Ubierna1, Mary P. Moyer2, Lucía Núñez1,3 and Carlos Villalobos1
1Institute of Molecular Biology and Genetics (IBGM), Spanish National Research Council (CSIC), Valladolid, Spain
2INCELL Corporation, San Antonio, TX, USA
3Department of Biochemistry and Molecular Biology and Physiology, University of Valladolid, Valladolid, Spain
Carlos Villalobos, email: [email protected]
Keywords: store-operated Ca2+ entry, store-operated currents, mitochondria, colorectal cancer, non-steroidal anti-inflammatory drugs
Received: May 10, 2017 Accepted: July 11, 2017 Published: July 21, 2017
Tumor cells undergo a critical remodeling of intracellular Ca2+ homeostasis that contribute to important cancer hallmarks. Store-operated Ca2+ entry (SOCE), a Ca2+ entry pathway modulated by mitochondria, is dramatically enhanced in colon cancer cells. In addition, most cancer cells display the Warburg effect, a metabolic switch from mitochondrial metabolism to glycolysis that provides survival advantages. Accordingly, we investigated mitochondria control of store-operated currents (SOCs) in two cell lines previously selected for representing human normal colonic cells and colon cancer cells. We found that, in normal cells, mitochondria are important for SOCs activity but they are unable to prevent current inactivation. In contrast, in colon cancer cells, mitochondria are dispensable for SOCs activation but are able to prevent the slow, Ca2+-dependent inactivation of SOCs. This effect is associated to increased ability of tumor cell mitochondria to take up Ca2+ due to increased mitochondrial potential (ΔΨ) linked to the Warburg effect. Consistently with this view, selected non-steroidal anti-inflammatory drugs (NSAIDs) depolarize mitochondria, inhibit mitochondrial Ca2+ uptake and promote SOC inactivation, leading to inhibition of both SOCE and cancer cell proliferation. Thus, mitochondria sustain store-operated currents in colon cancer cells but not in normal colonic cells and this effect is counteracted by selected NSAIDs providing a mechanism for cancer chemoprevention.
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