Abstract
The endoplasmic reticulum (ER) is a major intracellular calcium storage pool and a multifunctional organelle that accomplishes several calcium-dependent functions involved in many homeostatic and signaling mechanisms. Calcium is accumulated in the ER by Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA)-type calcium pumps. SERCA activity can determine ER calcium content available for intra-ER functions and for calcium release into the cytosol, and can shape the spatiotemporal characteristics of calcium signals. SERCA function therefore constitutes an important nodal point in the regulation of cellular calcium homeostasis and signaling, and can exert important effects on cell growth, differentiation and survival. In several cell types such as cells of hematopoietic origin, mammary, gastric and colonic epithelium, SERCA2 and SERCA3-type calcium pumps are simultaneously expressed, and SERCA3 expression levels undergo significant changes during cell differentiation, activation or immortalization. In addition, SERCA3 expression is decreased or lost in several tumor types when compared to the corresponding normal tissue. These observations indicate that ER calcium homeostasis is remodeled during cell differentiation, and may present defects due to decreased SERCA3 expression in tumors. Modulation of the state of differentiation of the ER reflected by SERCA3 expression constitutes an interesting new aspect of cell differentiation and tumor biology.
Highlights
The endoplasmic reticulum (ER) is a major intracellular calcium storage pool and a multifunctional organelle that accomplishes several calcium-dependent functions involved in many homeostatic and signaling mechanisms
These observations indicate that SERCA3 expression is lost during the multi-step process of colon carcinogenesis, that decreased SERCA3 expression is an early marker of colon tumorigenesis, and that SERCA3 expression is induced during colon and gastric cancer cell differentiation, a process during which the calcium homeostasis of the cell is modified
Investigation of the effect of individual viral proteins on Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA) expression using inducible expression vectors stably transfected into Epstein-Barr virus (EBV)-negative cells has shown, that whereas EBNA2 expression was without effect, SERCA3 expression was selectively down-regulated in cells expressing LMP-1 in the absence of any other EBV product [112]
Summary
Calcium is actively accumulated into the endoplasmic reticulum (ER) from the cytosol by. Calcium release from the ER combined with capacitative calcium influx from the extracellular space leads to markedly increased cytosolic calcium levels and the activation of key calcium-dependent enzymes such as protein kinase-C isoforms, calcineurin, calpains, calmodulin dependent kinases and other calmodulin binding proteins involved in cell activation [9,10]. Because calcium is accumulated in the ER exclusively by SERCA enzymes, SERCA-dependent calcium transport constitutes a key nodal point in the control of cell activation. When the calcium concentration dependency of calcium transport by various SERCA isoforms was compared, it has been shown that the apparent calcium affinity (KCa2+, as defined by the calcium concentration that leads to half-maximal induction of transport) of all SERCA3 isoforms is weaker (approximately 1.2 μM) than that of other isoforms, and in particular of SERCA2b (0.2 μM) [35,47,48,49,50,51]. With the aim of attracting attention to the remodeling of ER calcium homeostasis in cancer, we will briefly summarize here available data on the modulation of the expression of SERCA enzymes in several in vitro models of cancer cell differentiation, and on the patterns of SERCA3 protein expression in various human tumors and corresponding normal tissue in situ
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