Heme Oxygenase 1 Impairs Glucocorticoid Receptor Activity in Prostate Cancer

Abstract

Glucocorticoids are used during prostate cancer (PCa) treatment. However, they may also have the potential to drive castration resistant prostate cancer (CRPC) growth via the glucocorticoid receptor (GR). Given the association between inflammation and PCa, and the anti-inflammatory role of heme oxygenase 1 (HO-1), we aimed at identifying the molecular processes governed by the interaction 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. Hemin pre-treatment reduced Dex-induced GR activity in PC3 cells. Protein levels of FKBP51, a cytoplasmic GR-binding immunophilin, were significantly increased in Hemin+Dex treated cells, possibly accounting for lower GR activity. We also evaluated these treatments in vivo using PC3 tumors growing as xenografts. We found non-significant differences in tumor growth among treatments. Immunohistochemistry analyses revealed strong nuclear GR staining in almost all groups. We did not observe HO-1 staining in tumor cells, but high HO-1 reactivity was detected in tumor infiltrating macrophages. Our results suggest an association and crossed modulation between HO-1 and GR pathways.

Scavenging of Labile Heme by Hemopexin Is a Key Checkpoint in Cancer Growth and Metastases

“…This dose of heme neither affected body weight nor survival of mice (data not shown). In agreement with previously published results using the same in vivo model but less frequent and slightly lower doses of heme (Leonardi et al, 2019), we did not observe a significant difference in the overall tumor volume in mice treated with heme compared with untreated mice (Figure S2A). However, we showed increased local invasion (Figure 2A) and detected higher numbers of lymph node (LN) metastases after heme treatment (Figure 2B).…”

Role of HMOX1 Promoter Genetic Variants in Chemoresistance and Chemotherapy Induced Neutropenia in Children with Acute Lymphoblastic Leukemia

“…Interestingly, HO-1 overexpression has recently been reported to negatively modulate glucocorticoid receptor pathways in prostate cancer cells [86], and glucocorticoids (prednisone and dexamethasone) play an essential role in the treatment of acute lymphoblastic leukemia (ALL) [87]. In our study, we did not find a significant difference in prednisone response between patients with certain HMOX1 (GT)n genotype (data not shown).…”

α-Actinin-4 Promotes the Progression of Prostate Cancer Through the Akt/GSK-3β/β-Catenin Signaling Pathway

“…GR expression is reduced in primary PCa tissues compared to benign tissues; however, restored GR expression during the CRPC transition is critical for CRPC cell proliferation ( Puhr et al, 2018 ). Heme oxygenase 1 reduces cell proliferation by the inhibition of GR in PC3 cells ( Leonardi et al, 2019 ). Furthermore, replacement of reduced AR signaling with GR activation increases cell survival by inducing anti-apoptotic serum/glucocorticoid-regulated kinase 1 ( Isikbay et al, 2014 ).…”