Calcium mobilization from the endoplasmic reticulum (ER) into the cytosol is a key component of several signaling networks controlling
tumor cell growth, differentiation, or apoptosis. Sarco/endoplasmic reticulum
calcium transport
ATPases (SERCA-type
calcium pumps),
enzymes that accumulate
calcium in the ER, play an important role in these phenomena. We report that SERCA3 expression is significantly reduced or lost in colon
carcinomas when compared with normal colonic epithelial cells, which express this
enzyme at a high level. To study the involvement of SERCA
enzymes in differentiation, in this work differentiation of colon and
gastric cancer cell lines was initiated, and the change in the expression of SERCA
isoenzymes as well as intracellular
calcium levels were investigated. Treatment of the
tumor cells with
butyrate or other established differentiation inducing agents resulted in a marked and specific induction of the expression of SERCA3, whereas the expression of the ubiquitous SERCA2
enzymes did not change significantly or was reduced. A similar marked increase in SERCA3 expression was found during spontaneous differentiation of post-confluent Caco-2 cells, and this closely correlated with the induction of other known markers of differentiation. Analysis of the expression of the SERCA3 alternative splice
isoforms revealed induction of all three known iso-SERCA3 variants (3a, 3b, and 3c).
Butyrate treatment of the KATO-III
gastric cancer cells led to higher resting cytosolic
calcium concentrations and, in accordance with the lower
calcium affinity of SERCA3, to diminished ER
calcium content. These data taken together indicate a defect in SERCA3 expression in
colon cancers as compared with normal colonic epithelium, show that the
calcium homeostasis of the endoplasmic reticulum may be remodeled during cellular differentiation, and indicate that SERCA3 constitutes an interesting new
differentiation marker that may prove useful for the analysis of the phenotype of gastrointestinal
adenocarcinomas.