The effect of activated‐mitogen activated protein kinase (MAPK) activity on 1,25 dihydroxyvitamin D (1,25D)‐mediated gene transcription in colon cancer cells

Abstract

The active form of vitamin D (VD), 1,25D, induces anti‐cancer effects in many cell lines by activating the VD receptor (VDR). In cancer, MAPK pathways (ERK, JNK, p38) are activated and previous research shows that activated MAPK impairs 1,25D action in skin and prostate cell lines. To determine whether activating MAPK influences 1,25D action in colonocytes, Caco‐2 cells were pretreated with an agent that induces multiple MAPK pathways, As2O3, prior to 1,25D treatment. As2O3 decreased 1,25D‐mediated induction of CYP24 mRNA (−55%) but also decreased VDR mRNA levels by 50%. In contrast, a specific JNK activator, anisomycin, did not alter 1,25D‐mediated CYP24 mRNA induction indicating the effect of As2O3 was not due to JNK activation. KRAS activating mutations are common in colon cancer. Caco‐2 cells transfected with either a constitutively active (ca) KRAS plasmid or a caMEK1 plasmid have reduced 1,25 D‐induction of both 3XVDRE (−30%) and CYP24 promoter (−60%) reporter genes. Conversely, in HCT116 colon cancer cells with a RAS‐activating mutation 1,25D‐induced CYP24 mRNA was enhanced 285% by the MEK inhibition. These data demonstrate that a common mutation in colon cancer, i.e. KRAS activation, suppresses 1,25D action in colon cancer cells and may limit the chemopreventive effects of high vitamin D status.Supported by NIDDK Award DK54111 to JCF