Apc MIN modulation of vitamin D secosteroid growth control

Abstract

A central paradox of vitamin D biology is that 1α,25-(OH) ₂ D ₃ exposure inversely relates to colorectal cancer (CRC) risk despite a capacity for activation of both pro- and anti-oncogenic mediators including osteopontin (OPN)/CD44 and E-cadherin, respectively. Most sporadic CRCs arise from adenomatous polyposis coli (APC) gene mutation but understanding of its effects on vitamin D growth control is limited. Here we investigate effects of the Apc ^Min/+ genotype on 1α,25-(OH) ₂ D ₃ regulation of OPN/CD44/E-cadherin signalling and intestinal tumourigenesis, in vivo . In untreated Apc ^Min/+ versus Apc ^+/+ intestines, expression levels of OPN and its CD44 receptor were increased, whereas E-cadherin tumour suppressor signalling was attenuated. Treatment by 1α,25-(OH) ₂ D ₃ or rationally designed analogues (QW or BTW) enhanced OPN but inhibited expression of CD44, the OPN receptor implicated in cell growth. These treatments also enhanced E-cadherin tumour suppressor activity, characterized by inhibition of β-catenin nuclear localization, T-cell factor 1 and c-myelocytomatosis protein expression in Apc ^Min/+ intestine. All secosteroids suppressed Apc ^Min/+ -driven tumourigenesis although QW and BTW had lower calcium-related toxicity. Taken together, these data indicate that the Apc ^Min/+ genotype modulates vitamin D secosteroid actions to promote functional predominance of E-cadherin tumour suppressor activity within antagonistic molecular networks. APC heterozygosity may promote favourable tissue- or tumour-specific conditions for growth control by vitamin D secosteroid treatment.