Abstract
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.
Highlights
The Warburg effect, first reported by Otto Warburg [1], is an aberrant metabolic profile of most tumors characterized by a high glycolytic rate, despite the abundance of O2
As reported previously in other cell types, mitochondria depolarization limits the driving force for mitochondrial Ca2+ uptake [8, 9], unmasking their contribution to Store-operated Ca2+ entry (SOCE). These results suggest that mitochondria may control differentially SOCE in normal colonic and colon cancer cells
We have reported recently that colon cancer cells show a remarkable remodeling of intracellular Ca2+ homeostasis that contributes to cancer hallmarks including enhanced cell proliferation, cell invasion and resistance to cell death
Summary
The Warburg effect, first reported by Otto Warburg [1], is an aberrant metabolic profile of most tumors characterized by a high glycolytic rate, despite the abundance of O2. The Warburg effect confers numerous advantages to tumor cells, including enhanced proliferation, invasion and cell death resistance [2]. The mechanism underlying this effect is defective mitochondrial ATP synthesis associated to H+-ATP synthase dysfunction [3], resulting in enhanced anaerobic glycolysis. Another consequence of defective H+-ATP synthase activity that has not been addressed is the possible influence of the changes in mitochondrial potential (ΔѰ) to intracellular Ca2+ homeostasis. The ability of mitochondria to buffer entering Ca2+ may modulate the slow, Ca2+-dependent inactivation of Ca2+-release activated Ca2+ channels (CRAC) involved in store operated Ca2+ entry (SOCE) [8, 9] as well as of IP3 receptor channels responsible for Ca2+ release from intracellular stores at the endoplasmic reticulum (ER) [10]
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