Tajada Sendoa, Villalobos Carlos
Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid and Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain.
Front Pharmacol. 2020 Jul 7;11:968. doi: 10.3389/fphar.2020.00968. eCollection 2020.
Cancer, the second cause of death worldwide, is characterized by several common criteria, known as the "cancer hallmarks" such as unrestrained cell proliferation, cell death resistance, angiogenesis, invasion and metastasis. Calcium permeable channels are proteins present in external and internal biological membranes, diffusing Ca ions down their electrochemical gradient. Numerous physiological functions are mediated by calcium channels, ranging from intracellular calcium homeostasis to sensory transduction. Consequently, calcium channels play important roles in human physiology and it is not a surprise the increasing number of evidences connecting calcium channels disorders with tumor cells growth, survival and migration. Multiple studies suggest that calcium signals are augmented in various cancer cell types, contributing to cancer hallmarks. This review focuses in the role of calcium permeable channels signaling in cancer with special attention to the mechanisms behind the remodeling of the calcium signals. Transient Receptor Potential (TRP) channels and Store Operated Channels (SOC) are the main extracellular Ca source in the plasma membrane of non-excitable cells, while inositol trisphosphate receptors (IPR) are the main channels releasing Ca from the endoplasmic reticulum (ER). Alterations in the function and/or expression of these calcium channels, as wells as, the calcium buffering by mitochondria affect intracellular calcium homeostasis and signaling, contributing to the transformation of normal cells into their tumor counterparts. Several compounds reported to counteract several cancer hallmarks also modulate the activity and/or the expression of these channels including non-steroidal anti-inflammatory drugs (NSAIDs) like sulindac and aspirin, and inhibitors of polyamine biosynthesis, like difluoromethylornithine (DFMO). The possible role of the calcium permeable channels targeted by these compounds in cancer and their action mechanism will be discussed also in the review.
癌症是全球第二大致死原因，其具有几个共同特征，即所谓的“癌症标志”，如不受控制的细胞增殖、细胞死亡抗性、血管生成、侵袭和转移。钙通透性通道是存在于生物膜内外的蛋白质，可使钙离子沿其电化学梯度扩散。钙通道介导多种生理功能，从细胞内钙稳态到感觉转导。因此，钙通道在人体生理学中发挥着重要作用，越来越多的证据表明钙通道紊乱与肿瘤细胞的生长、存活和迁移有关也就不足为奇了。多项研究表明，各种癌细胞类型中的钙信号增强，促成了癌症标志。本综述重点关注钙通透性通道信号在癌症中的作用，特别关注钙信号重塑背后的机制。瞬时受体电位（TRP）通道和储存操纵性通道（SOC）是非兴奋性细胞质膜中主要的细胞外钙来源，而肌醇三磷酸受体（IPR）是从内质网（ER）释放钙的主要通道。这些钙通道的功能和/或表达的改变，以及线粒体的钙缓冲作用，都会影响细胞内钙稳态和信号传导，促使正常细胞转变为肿瘤细胞。据报道，几种可对抗多种癌症标志的化合物也能调节这些通道的活性和/或表达，包括舒林酸和阿司匹林等非甾体抗炎药（NSAIDs），以及多胺生物合成抑制剂，如二氟甲基鸟氨酸（DFMO）。本综述还将讨论这些化合物靶向的钙通透性通道在癌症中的可能作用及其作用机制。
