Calcium-ATPases: Gene disorders and dysregulation in cancer

Abstract

Ca(2+)-ATPases belonging to the superfamily of P-type pumps play an important role in maintaining low, nanomolar cytoplasmic Ca(2+) levels at rest and priming organellar stores, including the endoplasmic reticulum, Golgi, and secretory vesicles with high levels of Ca(2+) for a wide range of signaling functions. In this review, we introduce the distinct subtypes of Ca(2+)-ATPases and their isoforms and splice variants and provide an overview of their specific cellular roles as they relate to genetic disorders and cancer, with a particular emphasis on recent findings on the secretory pathway Ca(2+)-ATPases (SPCA). Mutations in human ATP2A2, ATP2C1 genes, encoding housekeeping isoforms of the endoplasmic reticulum (SERCA2) and secretory pathway (SPCA1) pumps, respectively, confer autosomal dominant disorders of the skin, whereas mutations in other isoforms underlie various muscular, neurological, or developmental disorders. Emerging evidence points to an important function of dysregulated Ca(2+)-ATPase expression in cancers of the colon, lung, and breast where they may serve as markers of differentiation or novel targets for therapeutic intervention. We review the mechanisms underlying the link between calcium homeostasis and cancer and discuss the potential clinical relevance of these observations. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.

Keywords: Breast cancer; Calcium ATPase; Calcium signaling; Golgi; Lactation; Secretory pathway.

Figure 1

Breast cancer cell lines from the NCI-60 human tumor cell line database [99] showing expression profiles for each of the Ca²⁺ pump isoforms depicted as Z score. Z-scores indicate how many standard deviations away a sample is from the mean expression value that was measured in a reference or control sample. Positive values reflect overexpression. The MCF7 and T47D cell lines are representative of the luminal A subtype and MDA-MB-231 and BT549 are representative of the claudin-low subtype. The database includes specific cell lines that are commonly utilized for cancer studies but is not comprehensive of all commercially available cancer cell lines. This database did not contain data for the SERCA1 isoform.

Figure 2

Colon cancer cell lines from the NCI-60 human tumor cell line database [99] showing the expression profiles for each of the Ca²⁺ pump isoforms depicted as Z score. HCT-116 is a colorectal carcinoma cell line derived from a late stage primary tumor. HCT-15 and HT-29 are colorectal adenocarcinoma cell lines that have been derived from an advanced stage primary tumors.