A remodeling of
calcium homeostasis has been identified as a characterizing feature of some
cancers. Possible consequences of this include alterations in many pivotal physiological responses including apoptosis, proliferation and gene transcription. An alteration in
calcium homeostasis can occur via changes in the expression of
proteins that transport
calcium and examples of
cancers where this is seen includes the prostate and breast. A specific
isoform of the
calcium efflux pump, plasma membrane Ca(2+)-
ATPase (PMCA) 4, is significantly upregulated during differentiation of the HT-29
colon cancer cell line suggesting that it may also be altered in
colon cancer. We now report that differentiated HT-29
colon cancer cells have pronounced plasma membrane PMCA4 localization, consistent with augmented
calcium efflux. Assessment of PMCA4 transcription in human
colon cancer samples suggests that PMCA4 is significantly (P < 0.000001) downregulated early in the progression of some
colon cancers as these cells become less differentiated. Inhibition of PMCA4 using
small interfering RNA did not induce cell death or augment sensitivity to the mitochondrial uncoupler
carbonyl cyanide 3-chlorophenylhydrazone (
CCCP) or
tumor necrosis factor-related apoptosis-inducing
ligand. Reversing the
colon cancer remodeling of PMCA4 by overexpression reduced cellular proliferation (P < 0.01) and downregulated transcription of the
calcium sensitive early response gene FOS. Our studies suggest that the remodeling of the
calcium signal in
colon cancer is associated with compromised
calcium efflux at a level that promotes proliferative pathways while avoiding increased sensitivity to apoptotic stimuli.