Heme Oxygenase 1 Impairs Glucocorticoid Receptor Activity in Prostate Cancer

LEONARDI DB, ANSELMINO N, BRANDANI JN, JAWORSKI FM, PÁEZ AV, MAZAIRA G, MEISS RP, NUÑEZ M, NEMIROVSKY SI, GIUDICE J, GALIGNIANA M, PECCI A, GUERON G, VAZQUEZ E, COTIGNOLA J.

INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES

IVYSPRING INT PUBL

Año: 2019

1449-2288

Glucocorticoids are used during prostate cancer (PCa) treatment. However, they may alsohave the potential to drive castration resistant prostate cancer (CRPC) growth via the glucocorticoidreceptor (GR). Given the association between inflammation and PCa, and the anti-inflammatoryrole of heme oxygenase 1 (HO-1), we aimed at identifying the molecular processes governed by theinteraction between HO-1 and GR. PCa-derived cell lines were treated with Hemin, Dexamethasone(Dex), or both. We studied GR gene expression by RTqPCR, protein expression by Western Blot,transcriptional activity using reporter assays, and nuclear translocation by confocal microscopy.We also evaluated the expression of HO-1, FKBP51, and FKBP52 by Western Blot. Heminpre-treatment reduced Dex-induced GR activity in PC3 cells. Protein levels of FKBP51, a cytoplasmicGR-binding immunophilin, were significantly increased in Hemin+Dex treated cells, possiblyaccounting for lower GR activity. We also evaluated these treatments in vivo using PC3 tumorsgrowing as xenografts. We found non-significant differences in tumor growth among treatments.Immunohistochemistry analyses revealed strong nuclear GR staining in almost all groups. We didnot observe HO-1 staining in tumor cells, but high HO-1 reactivity was detected in tumor infiltratingmacrophages. Our results suggest an association and crossed modulation between HO-1 andGR pathways