VDR independent induction of acid-sphingomyelinase by 1,23(OH) D in gastric cancer cells: Impact on apoptosis and cell morphology.

1 alpha,25-dihydroxyvitamin D (1,23(OH) D) is known to play a dual role in cancer, by promoting or inhibiting carcinogenesis via 1,23(OH) D receptor (VDR) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Fok I polymorphism of VDR may indirectly influence the receptor levels through autoregulation. The involvement of neutral sphingomyelinase in the non-classic VDR-mediated genomic pathway response to 1,23(OH) D treatment has been reported. Until now no information were reported about Fok I polymorphism of VDR in NCI-N87 human gastric cancer cells and the relation between acid sphingomyelinase and 1,23(OH) D. Herein, we showed that NCI-N87 human gastric cancer cells are homozygous for the Fok I 'C' allele; resulting in a three amino acid-truncated protein form of the VDR. Surprisingly 1,23(OH) D treatments strongly down-regulated the expression of VDR whereas acid sphingomyelinase and PTEN expression were upregulated. No changes of neutral sphingomyelinase expression were observed after 1,23(OH) D treatment, whereas acid sphingomyelinase activity increased. Furthermore 1,23(OH) D induced over-expression of caspase 8, CDKN2B, MAP3K5, cytochrome C apoptotic genes. Morphological analysis highlighted some very large round or oval cells and small cells with angular or fusiform extensions, confirmed by MIB-1 immunodetection and Hercep test. Taken together our results indicated that the action of 1,23(OH) D in gastric cancer cells was independent on 1,23(OH) D receptor and suggested the acid sphingomyelinase as a possible target to induce molecular events.