BACKGROUND:
Vitamin D is a chemopreventive agent that acts against colorectal carcinogenesis in vivo and in vitro through vitamin D receptor (VDR). Previous studies showed that stress-activated protein kinase JNKs (c-Jun NH2-terminal kinases) and p38 cooperated to activate VDR and increase vitamin D3-dependent growth inhibition in breast cancer cells. This study is to determine whether vitamin D-mediated inhibition of cell proliferation is associated with JNK1 in colorectal cancer cells.
METHODS AND RESULTS:
Human colon cancer cells were treated with calcitriol, an active vitamin D3. The results showed that calcitriol significantly inhibited cell proliferation and caused cell cycle arrest in HT29 cells, which... More
BACKGROUND:
Vitamin D is a chemopreventive agent that acts against colorectal carcinogenesis in vivo and in vitro through vitamin D receptor (VDR). Previous studies showed that stress-activated protein kinase JNKs (c-Jun NH2-terminal kinases) and p38 cooperated to activate VDR and increase vitamin D3-dependent growth inhibition in breast cancer cells. This study is to determine whether vitamin D-mediated inhibition of cell proliferation is associated with JNK1 in colorectal cancer cells.
METHODS AND RESULTS:
Human colon cancer cells were treated with calcitriol, an active vitamin D3. The results showed that calcitriol significantly inhibited cell proliferation and caused cell cycle arrest in HT29 cells, which was associated with induction of phosphorylated JNK1 (p-JNK). The induction of VDR and p-JNK by calcitriol was also observed in Caco-2 cells. Furthermore, VDR expression was significantly downregulated in JNK1-/- mouse intestinal epithelial cells, and VDR reporter activity was reduced in JNK1-/- mouse embryonic fibroblasts (MEFs). However, increasing activated JNK1 upregulated VDR expression and transcriptional activity in vitro. Moreover, JNK1 co-localized with VDR in nuclei and cytoplasm and physically bound together. Reduced expression of JNK1 and VDR in HT29 and Caco-2 cells and JNK1 absence in JNK1-/- MEFs attenuated calcitriol-mediated inhibition of cell proliferation.
CONCLUSION:
JNK1 physically and functionally interacted with VDR and positively regulated VDR expression at transcriptional and translational levels, which influenced calcitriol-mediated inhibition of cancer cell proliferation.
