HO-1 Interactors involved in the colonization of the bone niche: role of ANXA2 in prostate cancer progression

ANSELMINO NICOLAS; BIZZOTO, JUAN; SANCHIS, PABLO A; ORTIZ EMILIANO GERMAN; LABANCA ESTEFANIA; COTIGNOLA JAVIER; NAVONE NORA; GUERON GERALDINE; ELBA VAZQUEZ

Congreso; Advances in prostate cancer research; 2020

In prostate cancer (PCa), Heme Oxygenase 1 (HO-1), the rate limiting enzymein heme degradation may have a regulatory role beyond its enzymatic activity.The dissemination profile of PCa shows a tendency to develop in the bone,where tumoral cells interact with the microenvironment disrupting the bonetissue balance. In previous studies we screened for HO-1 interacting proteinsusing a proteomics approach. LC/ESI-MSMS analysis revealed the presence ofAnnexin 2 (ANXA2) among HO-1 interacting proteins. The aim of this study wasto analyze the relevance of ANXA2/HO-1 in PCa and bone metastasis. Weassessed ANXA2 levels using a co-culture transwell system of PCa cells (pre-treated or not with hemin, a HO-1 specific inducer) and the pre-osteoclasticRaw264.7 cell line. Under co-culture conditions, ANXA2 mRNA levels weresignificantly upregulated in PCa cells and downregulated in Raw264.7 cells.Immunofluorescence analysis unveiled a clear ANXA2 re-localization inRaw264.7 towards the cell cytosolic compartment under the same conditions,with a concomitant reduction in cell membrane immunostaining. This effect wassupported by the detection of a decrease in Ca 2+  concentration in theconditioned medium. Interestingly, HO-1 induction in tumor cells impaired botheffects, ANXA2 re-localization and Ca 2+  concentration reduction. These resultsindicate that paracrine factors from the bone niche modulate ANXA2 expressionin PCa cells, favoring in this way the anchorage and progression of the tumorcells in the skeletal metastatic site.To assess and validate the clinical significance of ANXA2/HO-1, we performeda bioinformatics analysis using public database repositories. We identified lowexpression of ANXA2, strongly associated with poor prognosis across differentPCa datasets. Multivariable analyses displayed high significant correlation withpoor prognosis independent from Gleason grade and PSA at diagnosis (HR:0.45; p=0.006). Low expression of HO-1 also correlated with poor prognosis.ANXA2/HO1 correlation was significant and positive and these genes appear tobehave in a dependent manner. Thus, ANXA2/HO1 rises as a critical axis inPCa.