Calcitriol, the hormonally active form of
Vitamin D, inhibits the growth and development of many
cancers through multiple mechanisms. Our recent research supports the contributory role of several new and diverse pathways that add to the mechanisms already established as playing a role in the actions of
calcitriol to inhibit the development and progression of
prostate cancer (PCa).
Calcitriol increases the expression of
insulin-like growth factor binding protein-3 (IGFBP-3), which plays a critical role in the inhibition of PCa cell growth by increasing the expression of the cell cycle inhibitor p21.
Calcitriol inhibits the
prostaglandin (PG) pathway by three actions: (i) the inhibition of the expression of
cyclooxygenase-2 (COX-2), the
enzyme that synthesizes PGs, (ii) the induction of the expression of 15-prostaglandin
dehydrogenase (15-PGDH), the
enzyme that inactivates PGs and (iii) decreasing the expression of EP and FP PG receptors that are essential for PG signaling. Since PGs have been shown to promote
carcinogenesis and progression of multiple
cancers, the inhibition of the PG pathway may add to the ability of
calcitriol to prevent and inhibit PCa development and growth. The combination of
calcitriol and non-steroidal anti-inflammatory drugs (
NSAIDs) result in a synergistic inhibition of PCa cell growth and offers a potential therapeutic strategy.
Mitogen activated protein kinase phosphatase 5 (MKP5) is a member of a family of
phosphatases that are negative regulators of MAP
kinases.
Calcitriol induces MKP5 expression in prostate cells leading to the selective dephosphorylation and inactivation of the stress-activated
kinase p38. Since p38 activation is pro-carcinogenic and is a mediator of
inflammation, this
calcitriol action, especially coupled with the inhibition of the PG pathway, contributes to the chemopreventive activity of
calcitriol in PCa.
Mullerian Inhibiting Substance (MIS) has been evaluated for its inhibitory effects in
cancers of the reproductive tissues and is in development as an anti-
cancer drug.
Calcitriol induces MIS expression in prostate cells revealing yet another mechanism contributing to the anti-
cancer activity of
calcitriol in PCa. Thus, we conclude that
calcitriol regulates myriad pathways that contribute to the potential chemopreventive and therapeutic utility of
calcitriol in PCa.