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.

Amyloid Beta A4 Precursor Protein-binding Family B Member 1 (FE65) Interactomics Revealed Synaptic Vesicle Glycoprotein 2A (SV2A) and Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2 (SERCA2) as New Binding Proteins in the Human Brain

“…SERCA2 is a protein that affects cellular calcium homeostasis (54,68) and was identified as an FE65 interacting protein in this study. SERCA2 was initially described as an intracellular pump located in the sarcoplasmic or endoplasmic reticula of muscle cells.…”

“…Knockdown of FE65 Sensitizes Cells to the Endoplasmic Reticulum Stressor Thapsigargin-SERCA2 and RYR3 are critical players in cellular calcium homeostasis (54,55). In order to test the hypothesis that FE65 affects intracellular calcium levels, we generated a stable FE65 knockdown cell line and measured cell viability following thapsigargin treat- .…”

Gypenosides Induce Apoptosis by Ca2+ Overload Mediated by Endoplasmic-Reticulum and Store-Operated Ca2+ Channels in Human Hepatoma Cells

“…31 Calcium is actively accumulated in the ER by SERCA-dependent calcium transport, the only calcium uptake mechanism in this organelle. 32 Significant changes in SERCA expression during cell differentiation or tumorigenesis can lead to modified ER calcium storage. Function-based genetic screening by systematic RNA interference identified STIM1 and Orai1 proteins as 2 essential molecular players in SOCs.…”

Calumenin and fibulin-1 on tumor metastasis: Implications for pharmacology

“…So far, several associated proteins of ER-resident calumenin have been reported, while the function of the calumenin isoforms in the Golgi apparatus is largely unknown. Sarco/endoplasmic reticulum calcium-ATPase (SERCA) is the sole calcium-ATPase that transfers calcium into the ER, and its deregulation is tightly related to disorders like muscle dysfunction and cancer [71]. Calumenin directly interacts with the forth luminal loop of SERCA2, and knockdown of calumenin significantly enhances cytosolic calcium transient amplitude and increases calcium sensitivity of SERCA2 [58].…”