DE SIERVI Adriana
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Bone response of prostate cancer: Over-expression of Heme oxygenase 1 (HO-1) in prostate cancer cells affects the redox balance and the number of active osteoblasts.
FERRANDO M; MEISS R; DE SIERVI A; NAVONE N; VAZQUEZ E
Congreso; 7th INTERNATIONAL MEETING ON HEME OXYGENASE & RELATED ENZYMES; 2012
Bone is the primary site of castrate-resistant progression of prostate cancer (PCa) and PCa is the only malignancy that produces bone-forming metastases. Osteoblasts produce factors that promote growth and survival of PCa cells; however, the molecular nature of this interaction is unknown. The aim of this work was to study the role of HO-1 in the interplay between PCa cells and bone. We used a co-culture model of PC3 cells, pre-treated or not with hemin, with primary mouse osteoblasts (PMO). HO-1 induction in PC3 cells abolished the PC3-induced loss of osteoblasts (H3-Timidine incorporation) and significantly increased mRNA levels of Dickkopf-1, a potent inhibitor of the Wnt/â-catenin pathway. Furthermore, PMO cycling cells were augmented when they were co-cultured with hemin pre-treated-PC3 cells. HO-1 induction in PCa cells significantly increased mRNA levels of bone proliferation markers (Runx-2 and Ki67) and diminished â-catenin protein expression in PMO. Moreover, HO-1 expression was up-regulated in PMO co-cultured with PC3 cells pre-treated with hemin. Additionally, HO-1 immunoreactivity was markedly increased in activated osteoblasts when PC3 cells pre-treated with hemin were co-cultured with mouse calvaria explants. InterestingIy, immunohistochemichal analysis of HO-1 expression using a tissue micro array of human castrate-resistant tumors growing as xenografts in wild type or castrated SCID mice demonstrated cytoplasmic HO-1 immunostaining in activated osteoblasts. Our findings revealed that HO-1 is involved in the bone response triggered by PCa cells and support the development of therapies targeting HO-1 for the advanced disease.