Glucocorticoid Receptor and β-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance

Abstract

Therapy resistance hinders the efficacy of anti-androgen therapies and taxane-based chemotherapy for advanced prostate cancer (PCa). Glucocorticoid receptor (GR) signaling mediates resistance to androgen receptor signaling inhibitors (ARSI) and has also been recently implicated in PCa resistance to docetaxel (DTX), suggesting a role in therapy cross-resistance. Like GR, β-catenin is upregulated in metastatic and therapy-resistant tumors and is a crucial regulator of cancer stemness and ARSI resistance. β-catenin interacts with AR to promote PCa progression. Given the structural and functional similarities between AR and GR, we hypothesized that β-catenin also interacts with GR to influence PCa stemness and chemoresistance. As expected, we observed that treatment with the glucocorticoid dexamethasone promotednuclear accumulation of GR and active β-catenin in PCa cells. Co-immunoprecipitation studies showed that GR and β-catenin interact in DTX-resistant and DTX-sensitive PCa cells. Pharmacological co-inhibition of GR and β-catenin, using the GR modulator CORT-108297 and the selective β-catenin inhibitor MSAB, enhanced cytotoxicity in DTX-resistant PCa cells grown in adherent and spheroid cultures and decreased CD44+/CD24–cell populations in tumorspheres. These results indicate that GR and β-catenin influence cell survival, stemness, and tumorsphere formation in DTX-resistant cells. Their co-inhibition could be a promising therapeutic strategy to overcome PCa therapy cross-resistance.

Wnt, glucocorticoid and cellular prion protein cooperate to drive a mesenchymal phenotype with poor prognosis in colon cancer

“…One major finding is that, in human, PRNP gene regulation is also highly modulated by glucocorticoid signaling. This observation fully fits in with the notion that the transcriptional response to Wnt-β-catenin signaling is highly context- and co-factor-dependent [ 30 ], and with the recent report that β-catenin partners with the GR to promote stemness properties of prostate cancer cells [ 50 ]. That PrP C levels are sensitive to corticoids has been previously documented in neutrophils by Mariante et al [ 51 ], but, to our knowledge, this is the first report that this also holds true in the context of cancer.…”

Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells

“…PC3, DU145, 22Rv1, and LNCaP cells were cultured in RPMI-1640 medium (Genesee Scientific, San Diego, CA, USA, Cat# 25-506), supplemented with 10% FBS, 1% Penicillin/Streptomycin (Corning, Glendale, AZ, USA, Cat# 30-002-CI), and Normocin 1G (Fisher Scientific, Pittsburgh, PA, USA, Cat# NC9390718). DTX-resistant PC3 (PC3-DR), DU145 (DU145-DR), and 22Rv1 (22Rv1-DR) cell lines were developed as previously described [ 25 , 29 ] and cultured in medium containing 10 nM DTX (LC Laboratories, Woburn, MA, USA, Cat# D-1000). For the development of LNCaP-ENZR cells, an androgen-depleted LNCaP subline was first generated through gradual replacement of FBS with charcoal-stripped FBS (CS-FBS) in culture.…”

“…Cells were transiently transfected for 72 h with scrambled (SCR) negative control (Integrated DNA Technologies, Coralville, IA, USA, Cat# 51-01-19-09), tri-silencer siRNA targeting GR (5′-AGAAUGACCUACAUCAAAGAGCUAG, 5′-GGAUACUAUACAAG CAGAACUGAGG, and 5′-GGAGAUCAUAUAGACAA UCAAGUGC), or siRNA targeting LEDGF/p75 (5′-AGACAGCAUGAGGAAGCGAUU). siRNA transfections (25 nM or 50 nM) were performed as described [ 25 , 38 ] and confirmed by immunoblotting.…”

“…Clinical evidence supports the presence of AR L702H mutation and enhanced GR expression in patients with PCa who acquired resistance to ARSI [ 12 , 14 , 16 ]. Although the role of GR signaling in ARSI resistance is well established [ 12 , 13 , 14 , 17 , 18 , 19 , 20 , 21 , 22 ], there is limited evidence linking GR signaling to PCa chemoresistance [ 20 , 23 , 24 , 25 ]. Emerging evidence supports the concept of therapy cross-resistance in PCa, wherein a particular therapy may lead to resistance to a subsequent therapy [ 26 ].…”

“…GR signaling may contribute to PCa chemoresistance via nuclear protein–protein interactions between GR and β-catenin [ 25 ] and the glucocorticoid-mediated upregulation of oncoproteins such as lens epithelium derived growth factor p75 (LEDGF/p75) and clusterin [ 24 ]. LEDGF/p75 is overexpressed in several human cancers, including PCa, and promotes tumor aggressive properties such as enhanced cancer cell proliferation, migration, clonogenic growth, tumorsphere formation, DNA repair, angiogenesis, and resistance to various chemotherapeutic agents [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ].…”