ALDH1A3 serves as a predictor for castration resistance in prostate cancer patients.
Aldehyde Oxidoreductases
/ metabolism
Androgen Antagonists
/ therapeutic use
Biomarkers, Tumor
/ metabolism
Disease Progression
Follow-Up Studies
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Male
Prognosis
Prostatic Neoplasms, Castration-Resistant
/ drug therapy
Retrospective Studies
Survival Rate
Tumor Cells, Cultured
Aldehyde dehydrogenase
Androgen deprivation therapy
Castration resistance prostate cancer
Resistance
Survival time
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
06 May 2020
06 May 2020
Historique:
received:
15
01
2020
accepted:
23
04
2020
entrez:
8
5
2020
pubmed:
8
5
2020
medline:
3
2
2021
Statut:
epublish
Résumé
Aldehyde dehydrogenase 1A3 (ALDH1A3) has been implicated in the survival and proliferation of prostate cancer cells. We retrospectively reviewed our patients with advanced disease on adjuvant hormonal therapy after prostatectomy. Time to castration resistance stage was documented. And Immunohistochemistry analysis for ALDH1A3 was performed for those patient samples on tissue microarray. Bioinformatics anslysis was used for RNA sequencing data of both primary prostate cancer and metastatic castration resistance prostate cancer (mCRPC) from online datasets. Crispr-Cas9 was used to knock out ALDH1A3 in prostate cancer luminal cells, and morphologic analysis as well as the Gene Set Enrichment Analysis (GSEA) were facilitated to discover the mechanisms of the resistance phenotype. We found that the patients with ALDH1A3 low expression had shorter time to progression to castration resistance compared with those of higher expression group on adjuvant hormonal therapy after radical prostatectomy. The ALDH1A3 knockout cells gradually acquired resistance to androgen deprivation therapy, a few cells have been found in knockout group showing as that the spindle-like luminal cells in charcoal stripped medium. Furthermore, PI3K pathway activation has been confirmed by Western blot. The PI3K pathway inhibitor BEZ235 has been demonstrated that the acquired ADT resistance by ALDH1A3 down regulation could be rescued by PI3K pathway inhibitor. These results suggested a novel function for ALDH1A3 in development of mCRPC, and indicated PI3K pathway inhibitor has the potential in the treatment of a subgroup of mCRPC patients.
Sections du résumé
BACKGROUND
BACKGROUND
Aldehyde dehydrogenase 1A3 (ALDH1A3) has been implicated in the survival and proliferation of prostate cancer cells.
METHODS
METHODS
We retrospectively reviewed our patients with advanced disease on adjuvant hormonal therapy after prostatectomy. Time to castration resistance stage was documented. And Immunohistochemistry analysis for ALDH1A3 was performed for those patient samples on tissue microarray. Bioinformatics anslysis was used for RNA sequencing data of both primary prostate cancer and metastatic castration resistance prostate cancer (mCRPC) from online datasets. Crispr-Cas9 was used to knock out ALDH1A3 in prostate cancer luminal cells, and morphologic analysis as well as the Gene Set Enrichment Analysis (GSEA) were facilitated to discover the mechanisms of the resistance phenotype.
RESULTS
RESULTS
We found that the patients with ALDH1A3 low expression had shorter time to progression to castration resistance compared with those of higher expression group on adjuvant hormonal therapy after radical prostatectomy. The ALDH1A3 knockout cells gradually acquired resistance to androgen deprivation therapy, a few cells have been found in knockout group showing as that the spindle-like luminal cells in charcoal stripped medium. Furthermore, PI3K pathway activation has been confirmed by Western blot. The PI3K pathway inhibitor BEZ235 has been demonstrated that the acquired ADT resistance by ALDH1A3 down regulation could be rescued by PI3K pathway inhibitor.
CONCLUSION
CONCLUSIONS
These results suggested a novel function for ALDH1A3 in development of mCRPC, and indicated PI3K pathway inhibitor has the potential in the treatment of a subgroup of mCRPC patients.
Identifiants
pubmed: 32375698
doi: 10.1186/s12885-020-06899-x
pii: 10.1186/s12885-020-06899-x
pmc: PMC7201787
doi:
Substances chimiques
Androgen Antagonists
0
Biomarkers, Tumor
0
Aldehyde Oxidoreductases
EC 1.2.-
aldehyde dehydrogenase (NAD(P)+)
EC 1.2.1.5
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
387Subventions
Organisme : Prostate cancer cohort study of Nanjing Medical University
ID : NMUC2018003A
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