Abstract
Prostate cancer (PCa) cells become castrate-resistant after initial tumor regression following castration-based lowering of testosterone (T). De-novo intra-tumoral steroid synthesis is a suggested biological mechanism of castration resistant PCa, but the regulators are unknown. Testicular T production is controlled by the luteinizing hormone/choriogonadotropin receptor (LHCGR). To elucidate the influence of LHCGR on PCa development the presence and effects of LHCGR in PCa and whether LHCGR in serum holds prognostic information in PCa patients is investigated. LHCGR expression was investigated by RT-PCR, WB, IHC, qPCR in PCa cell lines and prostatic tissue. Steroid production was measured in media from cell lines with LC-MS/MS and expression of steroidogenic enzymes with qPCR. Serum LHCGR (sLHCGR) was measured with ELISA in PCa patients (N = 157). Presence of LHCGR was established in prostatic tissue and PCa cell lines. Cell proliferation increased by 1.29-fold in LNCaP (P = 0.007) and 1.33-fold in PC-3 cells (P = 0.0007), when stimulated by luteinizing hormone. Choriogonadotropin stimulation decreased proliferation 0.93-fold in DU145 cells (P = 0.05), but none of the treatments altered steroid metabolite secretion. Low sLHCGR concentration was associated with a higher risk of biochemical failure after radical prostatectomy (HR = 3.05, P = 0.06) and castration resistance (HR = 6.92, P = 0.004) compared to high sLHCGR concentration. LHCGR is expressed in PCa and may exert a growth regulatory role in PCa derived cell lines. A potential prognostic role of sLHCGR for determining recurrence risk in PCa patients is found in this pilot study but needs verification in larger cohorts.
Highlights
Prostate cancer (PCa) cells are sensitive to testosterone (T) and the removal of T by medical or surgical castration results in tumor regression [1, 2]
A polymorphism in luteinizing hormone/choriogonadotropin receptor (LHCGR) that increase its activity was previously associated with decreased survival in men, a few reports have found LHCGR expression and luteinizing hormone (LH)-activity in PCa derived cell lines, and expression of human choriogonadotropin (hCG) in prostate tumors has been associated with poor prognosis, which all supports a role for LHCGR in PCa progression [13,14,15,16]
We tested the LHCGR antibodies on normal testis and PCa tissue specimens by IHC, which showed a specific membranous/cytoplasmic Leydig cell specific expression in the testis, while in human PCa tissue LHCGR was expressed in cytoplasm of the PCa cells and in the cytoplasm of all investigated cell lines (Fig 1C, S3 Fig)
Summary
Prostate cancer (PCa) cells are sensitive to testosterone (T) and the removal of T by medical or surgical castration results in tumor regression [1, 2]. A polymorphism in LHCGR that increase its activity was previously associated with decreased survival in men, a few reports have found LHCGR expression and LH-activity in PCa derived cell lines, and expression of hCG in prostate tumors has been associated with poor prognosis, which all supports a role for LHCGR in PCa progression [13,14,15,16]. This led us to investigate expression of LHCGR in PCa derived cell lines, PCa tissue from patients, and test the effect of LH and hCG on tumor growth and steroidogenesis. We measured LHCGR in serum from PCa patients to determine its potential as biomarker for disease progression
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