Calcium-ATPases: Gene disorders and dysregulation in cancer

Abstract

Ca2+-ATPases belonging to the superfamily of P-type pumps play an important role in maintaining low, nanomolar cytoplasmic Ca2+ levels at rest and priming organellar stores, including the endoplasmic reticulum, Golgi and secretory vesicles with high levels of Ca2+ for a wide range of signaling functions. In this review, we introduce the distinct subtypes of Ca2+-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 Ca2+-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 Ca2+-ATPase expression in cancers of the breast, 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.

Store Independent Ca2+Entry Regulates the DNA Damage Response in Breast Cancer Cells

“…However, constitutively high expression of SPCA2 was shown to promote tumor growth in receptor positive breast cancers through SICE and downstream Ca 2+ activation of the MAPK pathway. Thus, silencing of SPCA2 expression in ER+/PR+ xenograft models attenuated tumor formation in vitro and in vivo 8,14 .…”

“…Ca 2+ homeostasis is maintained by an array of membrane-embedded ion channels, ATPdriven pumps, and carrier proteins that rapidly move Ca 2+ across organelle or cell membranes. Dysregulation of the expression or activity of Ca 2+ transporters can produce abnormal elevation or depletion of cellular Ca 2+ levels, driving oncogenic gene expression, sustaining tumor proliferation and metastasis, and conferring chemoresistance and evasion of apoptosis 2,[7][8][9] . The presence of microcalcifications, which are radiographically dense deposits of calcium hydroxyapatite crystals in the soft tissue of breast, is an early sign of Ca 2+ dysregulation and potential malignancy in mammograms 10,11 .…”

Targeting calcium signaling in cancer therapy

“…SERCA is responsible for replenishing ER Ca 2+ stores, maintaining protein proper folding/maturation whereas dysregulated SERCA results in depleted or overloaded ER lumen Ca 2+ stores, increased ER stress, dysregulated chaperones and synthesis of lipids. Mutations and altered expression levels of SERCA isoforms have been identified in various cancers, such as cancers of colon, gastric, lung, myeloid leukemia and choroid plexus tumors 31 (Table 1). Overexpression of SERCA2 was found in colorectal cancer cells, which may drive proliferation and migration 32 .…”

A Ca2+-ATPase Regulates E-cadherin Biogenesis and Epithelial-Mesenchymal Transition in Breast Cancer Cells

“…In this study, we uncover a novel functional link between E-cadherin and SPCA2, one of two secretory pathway Ca 2+ -ATPases that transport Ca 2+ ions into the Golgi lumen for protein sorting, trafficking and quality control (12)(13)(14). Duplication of the SPCA gene (ATP2C) occurred during tetrapod evolution (15) and paved the way for acquisition of distinct functions.…”