Abstract
Inter-organelle membrane contact sites are emerging as major sites for the regulation of intracellular Ca2+ concentration and distribution. Here, extracellular stimuli operate on a wide array of channels, pumps, and ion exchangers to redistribute intracellular Ca2+ among several compartments. The resulting highly defined spatial and temporal patterns of Ca2+ movement can be used to elicit specific cellular responses, including cell proliferation, migration, or death. Plasma membrane (PM) also can directly contact mitochondria and endoplasmic reticulum (ER) through caveolae, small invaginations of the PM that ensure inter-organelle contacts, and can contribute to the regulation of numerous cellular functions through scaffolding proteins such as caveolins. PM and ER organize specialized junctions. Here, many components of the receptor-dependent Ca2+ signals are clustered, including the ORAI1-stromal interaction molecule 1 complex. This complex constitutes a primary mechanism for Ca2+ entry into non-excitable cells, modulated by intracellular Ca2+. Several contact sites between the ER and mitochondria, termed mitochondria-associated membranes, show a very complex and specialized structure and host a wide number of proteins that regulate Ca2+ transfer. In this review, we summarize current knowledge of the particular action of several oncogenes and tumor suppressors at these specialized check points and analyze anti-cancer therapies that specifically target Ca2+ flow at the inter-organelle contacts to alter the metabolism and fate of the cancer cell.
Highlights
From the 1940s, when a link between Calcium (Ca2+) and cancer was observed for the first time [1], until today, its centrality of Ca2+ action as second messenger in carcinogenesis and tumor progression has been confirmed [2].Ca2+ Modulation and Cancer TherapyUnder resting conditions, the cytosolic Ca2+ amount is maintained at a concentration of approximately 100 nM
stromal interaction molecule 1 (STIM1) has been shown to redistribute into clusters or puncta at endoplasmic reticulum (ER)-plasma membrane (PM) junctional sites [12], while the caveolar lipid rafts form flask-like invaginations 50–100 nm deep in the cell
Endoplasmic reticulum Ca2+ depletion plays a pivotal role in preventing mitochondrial Ca2+ overload and programmed cell death and, for this reason, it is the main target of the action of several oncogenes or oncosuppressors (Figure 1)
Summary
From the 1940s, when a link between Calcium (Ca2+) and cancer was observed for the first time [1], until today, its centrality of Ca2+ action as second messenger in carcinogenesis and tumor progression has been confirmed [2]. Increases in cytosolic Ca2+ concentration occur fundamentally through the entry of Ca2+ from the extracellular space This event is mediated by ligand-gated channels, such as the P2X purinergic-ionotropic receptor families [9], and transient receptor potential (TRP) channels. STIM1 has been shown to redistribute into clusters or puncta at ER-plasma membrane (PM) junctional sites [12], while the caveolar lipid rafts form flask-like invaginations 50–100 nm deep in the cell These structures, reducing the gap between the two membranes, facilitate SOCE channel interaction with ER-associated STIM1 puncta [13], and constitute a proper tether between the ER and the PM [13, 14]. The control mechanisms of intracellular Ca2+ homeostasis appear hierarchical, and their modulation and alteration as a cause or consequence of cancer induction and progression can change the sensitivity of cells to anti-tumor drugs
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