Mitochondria sustain store-operated currents in colon cancer cells but not in normal colonic cells: reversal by non-steroidal anti-inflammatory drugs

Abstract

// Miriam Hernández-Morales 1 , Diego Sobradillo 1 , Ruth A. Valero 1 , Eva Muñoz 1 , Daniel Ubierna 1 , Mary P. Moyer 2 , Lucía Núñez 1, 3 and Carlos Villalobos 1 1 Institute of Molecular Biology and Genetics (IBGM), Spanish National Research Council (CSIC), Valladolid, Spain 2 INCELL Corporation, San Antonio, TX, USA 3 Department of Biochemistry and Molecular Biology and Physiology, University of Valladolid, Valladolid, Spain Correspondence to: Carlos Villalobos, email: carlosv@ibgm.uva.es Keywords: store-operated Ca 2+ entry, store-operated currents, mitochondria, colorectal cancer, non-steroidal anti-inflammatory drugs Received: May 10, 2017      Accepted: July 11, 2017      Published: July 21, 2017 ABSTRACT Tumor cells undergo a critical remodeling of intracellular Ca 2+ homeostasis that contribute to important cancer hallmarks. Store-operated Ca 2+ entry (SOCE), a Ca 2+ 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, Ca 2+ -dependent inactivation of SOCs. This effect is associated to increased ability of tumor cell mitochondria to take up Ca 2+ 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 Ca 2+ 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.