The Loss of Sarco/Endoplasmic Reticulum Calcium Transport ATPase 3 Expression Is an Early Event during the Multistep Process of Colon Carcinogenesis

Abstract

Calcium accumulation in the endoplasmic reticulum is accomplished by sarco/endoplasmic reticulum calcium transport ATPases (SERCA enzymes). To better characterize the role of SERCA3 in colon carcinogenesis, its expression has been investigated in colonic epithelium, benign lesions, adenomas, and adenocarcinomas. In addition, the regulation of SERCA3 expression was analyzed in the context of the adenomatous polyposis coli/␤-catenin/T-cell factor 4 (TCF4) pathway and of specificity protein 1 (Sp1)-like factordependent transcription. We report that SERCA3 expression increased along the crypts as cells differentiated in normal colonic mucosa and in hyperplastic polyps, was moderately and heterogeneously expressed in colonic adenomas with expression levels inversely correlated with the degree of dysplasia, was barely detectable in well and moderately differentiated adenocarcinomas, and was absent in poorly differentiated tumors. Inhibition of Sp1-like factor-dependent transcription blocked SERCA3 expression during cell differentiation, and Calcium homeostasis of the endoplasmic reticulum (ER) is involved in several essential cell functions. Calcium stored in the ER is required for chaperone-assisted maturation of newly synthesized proteins transiting through the organelle. 1-3 Moreover, second messenger-induced calcium release from the ER through inositol-tris-phosphate-and ryanodine receptor-type calcium channels constitutes an integral part of many intracellular signal transduction pathways and networks. 4,5 Because ER calcium homeostasis is therefore involved in many constitutive or inducible cell functions, calcium accumulation into this organelle, assured by sarco/endoplasmic reticulum calcium transport ATPase (SERCA)-type calcium pumps is essential for numerous cellular activities such as secretion, neuronal plasticity, stress responses, proliferation, differentiation, or various forms of cell death. 6 -12 Three SERCA genes are known that code by alternative splicing several isoforms, the expression of which is tissue dependent and developmentally regulated. 13

Isoform-specific up-regulation of plasma membrane Ca2+ATPase expression during colon and gastric cancer cell differentiation

“…In addition, marked induction of the expression of the SERCA3 endoplasmic reticulum Ca 2+ ATPases has been shown earlier during megakaryocytopoiesis [88], during cell differentiation in various leukemia [21,42] and gastric/ colon cancer cells ( [21,22,89]. When taken together with data shown on PMCA expression in our present work, these observations indicate that the remodeling of cellular Ca 2+ homeostasis during differentiation is a phenomenon that concerns Ca 2+ sequestration in the ER, as well as Ca 2+ extrusion across the plasma membrane.…”

“…Furthermore, such treatments can induce or enhance cell differentiation in Friend erythroleukemia cells [94], in myeloid leukemia [95] and colon cancer [89]. This indicates that modulation of cellular Ca 2+ homeostasis during differentiation is not a simple passive consequence of the differentiation process.…”

Oncogenic K-Ras suppresses IP3-dependent Ca2+ release through remodeling of IP3Rs isoform composition and ER luminal Ca2+ levels in colorectal cancer cell lines

“…5D). Given that SERCA3 upregulation has been reported in cancer (Brouland et al, 2005), its expression was also investigated but found to be unchanged in cells lacking K-Ras G13D (supplementary material Fig. S1).…”

Full activation of mouse platelets requires ADP secretion regulated by SERCA3 ATPase–dependent calcium stores

“…10,11 SERCA mutations are associated with some cancers, [12][13][14] suggesting involvement in cell differentiation. 15 SERCA3 human mutations seem associated with type 2 diabetes. 16 Mouse SERCA2 knockouts are not viable at the homozygous state, but heterozygotes exhibit SERCA2a-type (defect in heart contractility and relaxation) 17 and SERCA2b-type defects, evocative of Darier syndrome.…”