TITLE:
Curcumin Inhibits Prostate Cancer Bone Metastasis by Up-Regulating Bone Morphogenic Protein-7 in Vivo
AUTHORS:
Thambi Dorai, Janane Diouri, Orla O’Shea, Stephen B. Doty
KEYWORDS:
Curcumin, Osteomimetic Properties, Bone Metastasis, Bone Morphogenic Protein-7, TGF-β, Prostate Cancer, Tumor Microenvironment
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.5 No.4,
March
31,
2014
ABSTRACT: A number of studies have
focused on the beneficial properties of Curcumin (diferuloyl methane, used in
South Asian cuisine and traditional medicine) such as the chemoprevention of
cancer. Recent studies have also indicated that this material has significant
benefits for the treatment of cancer and is currently undergoing several
clinical trials. We have been interested in the application of this compound as
a therapeutic agent for advanced prostate cancer, particularly the skeletal
complications in this malignancy. Our earlier work indicated that this compound
could inhibit the osteomimetic properties which occur in castration resistant
prostate cancer cells, by interfering with the common denominators between
these cancer cells and the bone cells in the metastatic tumor microenvironment,
namely the osteoblasts and the osteoclast. We predicted that curcumin could
break the vicious cycle of reciprocal stimulation that results in uncontrolled
osteolysis in the bony matrix. In this work, we have evaluated the potential of
this compound in inhibiting the bone metastasis of hormone refractory prostate
cancer cells in an established animal model. Our results strongly suggest that
curcumin modulates the TGF-βsignaling that occurs due to bone matrix
degradation by up-regulating the metastasis inhibitory bone morphogenic
protein-7 (BMP-7). This enhancement of BMP-7 in the context of TGF-β in the tumor microenvironment is shown
to enhance the mesenchymal-to-epithelial transition. Most importantly, we show
that as a result of BMP-7 up-regulation, a novel brown/beige adipogenic
differentiation program is also up-regulated which plays a role in the
inhibition of bone metastasis. Our results suggest that curcumin may subvert
the TGF-β signaling to an
alternative adipogenic differentiation program in addition to the previously
established interference with the osteomimetic properties, thus inhibiting the
bone metastatic processes in a chemopreventive as well as therapeutic setting.