Remodelado del Ca2+ Intracelular en el cáncer colorrectal: descripción, bases moleculares y consecuencias funcionales

Datos recientes sugieren que en el desarrollo del cáncer se produce un remodelado de la señal de Ca2+, sin embargo, no están claros cuáles son los mecanismos moleculares y funcionales del mismo. En el cáncer colorrectal, apenas existe información al respecto, por lo que nos propusimos estudiar en profundidad el remodelado del Ca2+ intracelular en esta patología. Los resultados muestran que en el cáncer colorrectal se produce un aumento de la entrada capacitativa de Ca2+, una mayor liberación de Ca2+, una mayor captación de Ca2+ por las mitocondrias y un menor contenido de Ca2+ de los depósitos intracelulares. A nivel molecular, estos cambios podrían deberse a un incremento de la expresión de TRPC1, ORAI1 y STIM1 y a la reducción de STIM2. Además, los resultados sugieren que el remodelado del Ca2+ intracelular puede contribuir a la proliferación y resistencia a la muerte de las células tumorales de colon.Departamento de Bioquímica, Biología Molecular y Fisiología. Instituto de Biología y Genética Molecular (IBGM

A reciprocal shift in transient receptor potential channel 1 (TRPC1) and stromal interaction molecule 2 (STIM2) contributes to Ca2+remodeling and cancer hallmarks in colorectal carcinoma cells

Producción CientíficaWe have investigated the molecular basis of intracellular Ca2+ handling in human colon carcinoma cells (HT29) versus normal human mucosa cells (NCM460) and its contribution to cancer features. We found that Ca2+ stores in colon carcinoma cells are partially depleted relative to normal cells. However, resting Ca2+ levels, agonist-induced Ca2+ increases, store-operated Ca2+ entry (SOCE), and store-operated currents (ISOC) are largely enhanced in tumor cells. Enhanced SOCE and depleted Ca2+ stores correlate with increased cell proliferation, invasion, and survival characteristic of tumor cells. Normal mucosa cells displayed small, inward Ca2+ release-activated Ca2+ currents (ICRAC) mediated by ORAI1. In contrast, colon carcinoma cells showed mixed currents composed of enhanced ICRAC plus a nonselective ISOC mediated by TRPC1. Tumor cells display increased expression of TRPC1, ORAI1, ORAI2, ORAI3, and STIM1. In contrast, STIM2 protein was nearly depleted in tumor cells. Silencing data suggest that enhanced ORAI1 and TRPC1 contribute to enhanced SOCE and differential store-operated currents in tumor cells, whereas ORAI2 and -3 are seemingly less important. In addition, STIM2 knockdown decreases SOCE and Ca2+ store content in normal cells while promoting apoptosis resistance. These data suggest that loss of STIM2 may underlie Ca2+ store depletion and apoptosis resistance in tumor cells. We conclude that a reciprocal shift in TRPC1 and STIM2 contributes to Ca2+ remodeling and tumor features in colon cancer.Ministerio de Economía, Industria y Competitividad (grants BFU2009-08967 and BFU2012-37)Junta de Castilla y León (grant VA145U13

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

Producción CientíficaTumor 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.Ministerio de Economía, Industria y Competitividad (grant BFU2015-70131R)Junta de Castilla y León (grant VA145U13