Endoplasmic reticulum calcium pumps and cancer

Abstract

Endoplasmic reticulum calcium homeostasis is involved in a multitude of signaling, as well as "house-keeping" functions that control cell growth, differentiation or apoptosis in every human/eukaryotic cell. Calcium is actively accumulated in the endoplasmic reticulum by Sarco/Endoplasmic Reticulum Calcium transport ATPases (SERCA enzymes). SERCA-dependent calcium transport is the only calcium uptake mechanism in this organelle, and therefore the regulation of SERCA function by the cell constitutes a key mechanism to adjust calcium homeostasis in the endoplasmic reticulum depending on the cell type and its state of differentiation. The direct pharmacological modulation of SERCA activity affects cell differentiation and survival. SERCA expression levels can undergo significant changes during cell differentiation or tumorigenesis, leading to modified endoplasmic reticulum calcium storage. In several cell types such as cells of hematopoietic origin or various epithelial cells, two SERCA genes (SERCA2 and SERCA3) are simultaneously expressed. Expression levels of SERCA3, a lower calcium affinity calcium pump are highly variable. In several cell systems SERCA3 expression is selectively induced during differentiation, whereas during tumorigenesis and blastic transformation SERCA3 expression is decreased. These observations point at the existence of a cross-talk, via the regulation of SERCA3 levels, between endoplasmic reticulum calcium homeostasis and the control of cell differentiation, and show that endoplasmic reticulum calcium homeostasis itself can undergo remodeling during differentiation. The investigation of the anomalies of endoplasmic reticulum differentiation in tumor and leukemia cells may be useful for a better understanding of the contribution of calcium signaling to the establishment of malignant phenotypes.