Hmox-1 deficiency impairs bone turn over and remodeling molecular implications for prostate cancer bone metastasis

VAZQUEZ ELBA; COTIGNOLA, JAVIER HERNÁN; VALACCO, PIA; BIZZOTO, JUAN; ANSELMINO, NICOLÁS; NAVONE, NORA; STARBUCK M; ZENCLUSSEN A; GUERON GUERALDINE

Mar del Plata

Congreso; LXIII REUNION ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACION CLINICA; 2018

SAIC

Bone is frequently the unique site of prostate cancer (PCa) progression. Uponmetastases, tumor cells interact with the bone microenvironment interrupting the tissue balance. Heme oxygenase-1 (HO-1) appears as a potential target in PCa maintaining the cellular homeostasis. Our hypothesis is that HO-1 modulation in bone cells is implicated in the capacity of PCa cells to metastasize to bone. We aimed at: assessing the physiological impact of Hmox-1 gene Knock-out (KO) on bone metabolism in vivo; determining the transcriptional landscape of genes involved in tumorigenesis and bone remodeling growing in co-culture systems of PCa cells with primary mouse osteoblasts (PMOs) isolated from BALB/c Hmox-1 +/+, +/- and -/- mice and analyzing whole secretomes from co-cultures of PCa cells with bone progenitor cells to evaluate key osteogenic factors favoring the aggressive phenotype in PCa. Histomorphometric analysis of bones from transgenic KO Hmox-1 mice exhibited significant decrease in bone density with reduced bone remodeling parameters. Correlation between the expression of Hmox-1 and Runx2, Col1a1, Mcsf1 and Opg (RT-qPCR) was observed in PMOs. FACS studies showed two populations of PMOs with different ROS-levels. The high ROS-levels population was increased in PMOs Het compared with WT, but was strong reduced in PMOs KO, showing restrained ROS tolerance in KO cells. PMOs gene expression was altered by co-culture with PC3 cells showing a more osteoclastic profile. Moreover, HO-1 induction in PCa cells growing in co-culture with bone progenitor cells (MC3T3, RAW 264.7) reflected a significant modulation of key bone markers (PTHrP, OPG and RANK) associated with proliferation and differentiation. Secretome analysis (ESI MS/MS) of conditioned media form these co-cultures revealed markers for PCa Neuro-Endocrine differentiation as compared to secretomes form controls. In summary, we showcase that the extent of HO-1 expression intervenes in bone remodeling and disrupts the communication between bone and prostate tumor cells.