Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain.
Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain; Departamento de Bioquímica STIM Biología Molecular STIM Fisiología, Universidad de Valladolid, Valladolid, Spain.
Cell Calcium. 2019 Jul;81:59-66. doi: 10.1016/j.ceca.2019.06.003. Epub 2019 Jun 7.
Colon cancer cells, like other types of cancer cells, undergo the remodeling of the intracellular Ca homeostasis that contributes to cancer cell hallmarks including enhanced cell proliferation, migration, and survival. Colon cancer cells display enhanced store-operated Ca entry (SOCE) compared with their non-cancer counterparts. Colon cancer cells display an abnormal expression of SOCE molecular players including Orai1 and TRPC1 channels, and the stromal interacting molecule (STIM) 1 and 2. Interestingly, upregulation of Orai1 and TRPC1 channels and their contribution to SOCE are associated with cancer malignancy in colon cancer cells. In a specific cellular model of colon cancer, whereas in non-cancer colon cells SOCE is composed of the Ca release activated (CRAC) currents, in colon cancer cells SOCE is composed of CRAC- and cationic, non-selective store operated (SOC) currents. Former SOCs are mediated by TRPC1 channels. Moreover, colon cancer cells also display dysregulation of the expression of 1,4,5-triphosphate receptors (IPR) that could contribute to the enhanced SOCE. Another important factor underlying the enhanced SOCE is the differential mitochondrial modulation of the CRAC and SOC currents in non-cancer and colon cancer cells. In colon cancer cells, mitochondria take up more Ca that prevent the Ca-dependent inactivation of the SOCs, leading to sustained Ca entry. Notably, the inhibition of SOCE in cancer colon cells abolishes their cancer hallmarks. Robust evidence has shown the efficiency of non-steroidal anti-inflammatory drugs (NSAIDs) and difluoromethylornithine (DFMO) to reverse the enhanced cell proliferation, migration, and apoptosis resistance of cancer cells. In colon cancer cells, both NSAIDs and DFMO decrease SOCE, but they target different molecular components of SOCE. NSAIDs decrease the Ca uptake by mitochondria, limiting their ability to prevent the Ca-dependent inactivation of the SOCs that underlie SOCE. On the other hand, DFMO inhibits the expression of TRPC1 channels in colon cancer cells, eliminating their contribution to SOCE. The identification of players of SOCE in colon cancer cells may help to better understand the remodeling of the Ca homeostasis in cancer. Importantly, the use of different pharmacological tools that target different SOCE molecular players in colon cancer cells may play a pivotal role in designing better chemoprevention strategies.
结肠癌细胞与其他类型的癌细胞一样，经历细胞内钙稳态的重塑，这有助于包括增强细胞增殖、迁移和存活在内的癌症特征。与非癌细胞相比，结肠癌细胞显示出增强的储存操作钙内流（SOCE）。结肠癌细胞显示出异常表达 SOCE 分子，包括 Orai1 和 TRPC1 通道以及基质相互作用分子（STIM）1 和 2。有趣的是，Orai1 和 TRPC1 通道的上调及其对 SOCE 的贡献与结肠癌细胞的癌症恶性有关。在结肠癌细胞的特定细胞模型中，非癌细胞中的 SOCE 由钙释放激活（CRAC）电流组成，而在结肠癌细胞中，SOCE 由 CRAC 和阳离子非选择性储存操作（SOC）电流组成。前 SOC 由 TRPC1 通道介导。此外，结肠癌细胞还显示出三磷酸肌醇受体（IPR）表达的失调，这可能有助于增强 SOCE。增强 SOCE 的另一个重要因素是 CRAC 和 SOC 电流在非癌细胞和结肠癌细胞中的差异线粒体调节。在结肠癌细胞中，线粒体摄取更多的 Ca2+，防止 SOC 的 Ca2+依赖性失活，从而导致持续的 Ca2+内流。值得注意的是，抑制癌症结肠细胞中的 SOCE 会消除其癌症特征。大量证据表明，非甾体抗炎药（NSAIDs）和二氟甲基鸟氨酸（DFMO）能够逆转癌症细胞的增殖、迁移和抗凋亡能力增强。在结肠癌细胞中，NSAIDs 和 DFMO 均降低 SOCE，但它们针对 SOCE 的不同分子成分。NSAIDs 降低了线粒体摄取的 Ca2+，限制了其防止 SOC 钙依赖性失活的能力，而 SOC 是 SOCE 的基础。另一方面，DFMO 抑制结肠癌细胞中 TRPC1 通道的表达，消除了其对 SOCE 的贡献。SOCE 分子在结肠癌细胞中的鉴定可能有助于更好地理解癌症中钙稳态的重塑。重要的是，使用针对结肠癌细胞中不同 SOCE 分子的不同药理工具可能在设计更好的化学预防策略中发挥关键作用。
