Targeting the glucocorticoid receptor signature gene Mono Amine Oxidase-A enhances the efficacy of chemo- and anti-androgen therapy in advanced prostate cancer.
Martin PuhrAndrea EigentlerFlorian HandleHubert HacklChristian PlonerIsabel HeideggerGeorg SchaeferMaximilian P BrandtJulia HoeferGabri Van der PluijmHelmut KlockerPublished in: Oncogene (2021)
Despite increasing options for treatment of castration-resistant prostate cancer, development of drug resistance is inevitable. The glucocorticoid receptor (GR) is a prime suspect for acquired therapy resistance, as prostate cancer (PCa) cells are able to increase GR signaling during anti-androgen therapy and thereby circumvent androgen receptor (AR)-blockade and cell death. As standard AR-directed therapies fail to block the GR and GR inhibitors might result in intolerable side effects, the identification of GR signature genes, which are better suited for a targeted approach, is of clinical importance. Therefore, the specific epithelial and stromal GR signature was determined in cancer-associated fibroblasts as well as in abiraterone and enzalutamide-resistant cells after glucocorticoid (GC) treatment. Microarray and ChIP analysis identified MAO-A as a directly up-regulated mutual epithelial and stromal GR target, which is induced after GC treatment and during PCa progression. Elevated MAO-A levels were confirmed in in vitro cell models, in primary tissue cultures after GC treatment, and in patients after neoadjuvant chemotherapy with GCs. MAO-A expression correlates with GR/AR activity as well as with a reduced progression-free survival. Pharmacological MAO-A inhibition combined with 2nd generation AR signaling inhibitors or chemotherapeutics results in impaired growth of androgen-dependent, androgen-independent, and long-term anti-androgen-treated cells. In summary, these findings demonstrate that targeting MAO-A represents an innovative therapeutic strategy to synergistically block GR and AR dependent PCa cell growth and thereby overcome therapy resistance.
Keyphrases
- prostate cancer
- induced apoptosis
- cell death
- cell cycle arrest
- neoadjuvant chemotherapy
- radical prostatectomy
- squamous cell carcinoma
- gene expression
- cell therapy
- cancer therapy
- stem cells
- newly diagnosed
- genome wide
- poor prognosis
- signaling pathway
- combination therapy
- dna methylation
- mass spectrometry
- oxidative stress
- bone marrow
- early stage
- locally advanced
- transcription factor
- binding protein
- radiation therapy
- cell proliferation
- single cell
- high resolution
- extracellular matrix
- photodynamic therapy
- bioinformatics analysis
- endoplasmic reticulum stress
- mesenchymal stem cells
- pi k akt
- genome wide identification
- liquid chromatography