IP(3) Receptor-Mediated Calcium Signaling and Its Role in Autophagy in Cancer.
IP(3) Receptor-Mediated Calcium Signaling and Its Role in Autophagy in Cancer.
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DOI：
10.3389/fonc.2017.00140
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发表时间：
2017
影响因子：
4.7
通讯作者：
Bultynck G
中科院分区：
文献类型：
--
作者：
Kania E;Roest G;Vervliet T;Parys JB;Bultynck G
钙离子（Ca 2+）在协调不同的细胞过程中发挥着复杂的作用，包括细胞死亡和存活。为了触发信号级联，细胞内Ca 2+在细胞质和主要的Ca 2+储存、内质网（ER）、线粒体和溶酶体之间进行改组。在控制Ca 2+信号中的关键作用归因于1，4，5-三磷酸肌醇（IP 3）受体（IP 3 Rs），即ER中的主要Ca 2+释放通道。IP 3Rs可以将Ca 2+转移到线粒体，从而不仅刺激核心代谢途径，而且增加凋亡敏感性并抑制基础自噬。另一方面，IP 3诱导的Ca 2+释放通过提供在各种细胞应激（包括营养饥饿、雷帕霉素抑制的化学机制靶标或药物处理）下执行自噬所需的胞质Ca 2+来增强自噬通量。类似地，IP 3R能够放大来自溶酶体的Ca 2+信号，因此，响应于溶酶体通道激活而影响自噬通量。此外，通过IP 3Rs间接调节Ca 2+释放也可以通过控制ER的肌浆网/内质网Ca 2 + ATP酶Ca 2+泵来实现。考虑到自噬在癌症发展和进展以及对抗癌治疗的反应中的复杂作用，很明显，充分了解IP 3R及其细胞背景在这种疾病中的作用是很重要的。在依赖于ER-线粒体Ca 2+燃料的癌细胞中，IP 3R抑制通过涉及增强的自噬或有丝分裂灾难的机制导致癌细胞死亡。此外，IP 3R是几种致癌基因和肿瘤抑制因子的靶标，并且这些基因的功能丧失，如在许多癌症类型中发生的，可以导致修饰的Ca 2+转运到线粒体和调节自噬通量的水平。类似地，IP 3R介导的自噬上调可以保护一些癌细胞免受自然杀伤细胞诱导的杀伤。因此，IP 3R参与自噬和凋亡的调节，直接影响癌细胞生物学，并有助于肿瘤病理学的分子基础。
Calcium ions (Ca2+) play a complex role in orchestrating diverse cellular processes, including cell death and survival. To trigger signaling cascades, intracellular Ca2+ is shuffled between the cytoplasm and the major Ca2+ stores, the endoplasmic reticulum (ER), the mitochondria, and the lysosomes. A key role in the control of Ca2+ signals is attributed to the inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), the main Ca2+-release channels in the ER. IP3Rs can transfer Ca2+ to the mitochondria, thereby not only stimulating core metabolic pathways but also increasing apoptosis sensitivity and inhibiting basal autophagy. On the other hand, IP3-induced Ca2+ release enhances autophagy flux by providing cytosolic Ca2+ required to execute autophagy upon various cellular stresses, including nutrient starvation, chemical mechanistic target of rapamycin inhibition, or drug treatment. Similarly, IP3Rs are able to amplify Ca2+ signals from the lysosomes and, therefore, impact autophagic flux in response to lysosomal channels activation. Furthermore, indirect modulation of Ca2+ release through IP3Rs may also be achieved by controlling the sarco/endoplasmic reticulum Ca2+ ATPases Ca2+ pumps of the ER. Considering the complex role of autophagy in cancer development and progression as well as in response to anticancer therapies, it becomes clear that it is important to fully understand the role of the IP3R and its cellular context in this disease. In cancer cells addicted to ER–mitochondrial Ca2+ fueling, IP3R inhibition leads to cancer cell death via mechanisms involving enhanced autophagy or mitotic catastrophe. Moreover, IP3Rs are the targets of several oncogenes and tumor suppressors and the functional loss of these genes, as occurring in many cancer types, can result in modified Ca2+ transport to the mitochondria and in modulation of the level of autophagic flux. Similarly, IP3R-mediated upregulation of autophagy can protect some cancer cells against natural killer cells-induced killing. The involvement of IP3Rs in the regulation of both autophagy and apoptosis, therefore, directly impact cancer cell biology and contribute to the molecular basis of tumor pathology.