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Impact of BCL2 Overexpression in castration resistance prostate cancer progression I

ABSTRACT: In analyzing transcriptomic data from a clinical trial of neoadjuvant-intensive Androgen Deprivation Therapy, we observed increased mRNA expression of the hallmark antiapoptotic gene BCL2 in the prostate tumors of treated patients versus those of untreated patients. We showed that BCL2 overexpressed LNCaP cells exhibited resistance to prolonged androgen deprivation therapy, indicating that BCL2-overexpression leads to castration resistance and cellular plasticity.Our study indicating that BCL2 overexpression may act as a major driver of early castration resistance in prostate cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273736 | GEO | 2025/05/15

REPOSITORIES: GEO

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Project description:Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen-deprivation remain poorly described despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild type mouse prostates a rare population of luminal progenitor cells that we called LSCmed according to their FACS profile (Lin?/Sca-1+/CD49fmed). Here we investigated the prevalence and castration resistance of LSCmed in various mouse models of prostate tumorigenesis. In intact mice, we show that LSCmed prevalence remains low (5-10% of epithelial cells) when prostatic androgen receptor signaling unaltered (malignant Hi-Myc mice) but significantly increases in models exhibiting reduced prostatic androgen receptor signaling, rising up to 30% in premalignant tumors (Pb-PRL mice) and to >80% in castration-resistant prostate tumors driven by Pten loss (Ptenpc-/- mice). LSCmed tolerance to androgen deprivation was demonstrated by their persistence (Ptenpc-/-) or further enrichment (Pb-PRL) 2-3 weeks after castration as evidenced by FACS analysis. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene-expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signaling is markedly decreased, which explains why LSCmed tolerate androgen-deprivation. This also enlightens why Ptenpc-/- tumors are castration-resistant since LSCmed represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSCmed on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSCmed in various mouse prostate specimens. In castrated Ptenpc-/- prostates, BrdU staining revealed massive proliferation of CK4+ cells, further demonstrating their key role in castration-resistant prostate cancer progression. In all, this study identifies LSCmed as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer.

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Impact of BCL2 Overexpression in castration resistance prostate cancer progression I

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