Abstract
BackgroundAldehyde dehydrogenase 1A3 (ALDH1A3) has been implicated in the survival and proliferation of prostate cancer cells.MethodsWe 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.ResultsWe 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.ConclusionThese 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.
Highlights
Aldehyde dehydrogenase 1A3 (ALDH1A3) has been implicated in the survival and proliferation of prostate cancer cells
aldehyde dehydrogenase family 1 member A3 (ALDH1A3) negative predicted castrationresistant prostate cancer (CRPC) in patients on adjuvant Androgen deprivation therapy (ADT) Our earlier work has demonstrated that ALDH1A3 highly expressed in human prostate, which had a strong correlation with primary prostate cancer luminal signature and could be a potential biomarker of AR signaling pathway
We retrospectively reviewed 79 patients with advanced disease who underwent radical prostatectomy followed by adjuvant hormonal therapy in our center
Summary
Aldehyde dehydrogenase 1A3 (ALDH1A3) has been implicated in the survival and proliferation of prostate cancer cells. Androgen deprivation therapy (ADT) is the standard of care for advanced prostate cancer or progression after. The Stand Up to Cancer (SU2C) prostate cancer Dream Team sequenced 150 metastatic castration resistant prostate cancer samples [3], which benefits a lot to investigate the mechanisms of castration resistance in this disease. In the primary prostate cancer, the expression of this gene correlated with AR pathway and luminal markers. For those with advanced disease after radical prostatectomy who underwent adjuvant androgen deprivation therapy, negative ALDH1A3 expression predicted as shorter time for castration resistance upon hormonal therapy
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