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Microarray transcriptomic data from LNCaP cells treated with vehicle, 10 nM bufalin or 20 nM bufalin for 24 h

ABSTRACT: Bufalin is a major cardiotonic compound in the traditional Chinese medicine Chanshu preparations of toad skin secretions. Cell culture studies have suggested anti-cancer potential involving multiple cellular processes including differentiation, apoptosis, senescence and angiogenesis. In prostate cancer (PCa) cell models, P53-dependent and independent caspase-mediated apoptosis and androgen receptor (AR) antagonism have been described for bufalin at micromolar concentrations. Since pharmacokinetic study in humans indicated single nanomolar bufalin was safely achievable in the peripheral circulation, we evaluated its cellular activity within range with the AR-positive, P53-wild type and PTEN-negative human LNCaP PCa cells in vitro. Our data show that bufalin induced caspase-mediated apoptosis at 10 nanomolar or higher exposure concentration with concomitant suppression of AR protein and its best known target prostate specific antigen (PSA) and steroid receptor co-activator 1 and 3 (SRC-1, SRC-3). Bufalin exposure induced protein abundance of P53 (not mRNA) and P21Cip1, G2 arrest and increased senescence-like phenotype (SA-galactosidase). Small interference RNA knocking down of P53 attenuated bufalin-induced senescence, whereas knocking down of P21Cip1 exacerbated bufalin-induced caspase-mediated apoptosis. In vivo, daily i.p. injection of bufalin (1.5 mg/kg body weight) for 9 weeks delayed LNCaP subcutaneous xenograft tumor growth in NSG SCID mice with a 67% decrease of final weight without affecting body weight. Tumors from bufalin-treated mice exhibited increased phospho-P53 and SA-galactosidase without detectable caspase-mediated apoptosis or suppression of AR and PSA. Our data suggest potential applications of bufalin in adjuvant therapy of PCa recurrence in patients or chemoprevention of prostate carcinogenesis, engaging a selective activation of P53-senescence.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118261 | GEO | 2018/08/13

REPOSITORIES: GEO

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Project description:The bipolar androgen therapy (BAT) to treat prostate cancer includes cycles of supraphysiological androgen levels (SAL) under continuous androgen deprivation therapy (ADT). We showed previously that SAL induces cellular senescence in androgen-sensitive PCa cells and ex vivo in PCa tumor samples from patients that underwent radical prostatectomy. Here, we show that SAL induces cellular senescence in both, castration sensitive (CSPC) LNCaP and castration resistant PCa (CRPC) C4-2 cells through the cell cycle inhibitor p15. Treatment with the Akt inhibitor (Akti) potently inhibited SAL-induced expression of p15 and cellular senescence in both cell lines. Proximity ligation assays (PLA) combined with high-resolution laser-scanning microscopy indicate that SAL promotes interaction of endogenous androgen receptor (AR) with endogenous Akt in cytoplasm as well as in nucleus after 72 hours hormone treatment. This suggests that the AR interacts with Akt also in a long-term manner. Transcriptome sequencing (RNA-seq) comparing the SAL-induced transcriptomes of LNCaP with C4-2 cells as well as of Akti treated cells revealed landscapes for cell senescence. Interestingly, one of the identified genes is the lncRNASAT1. SAL treatment of native patient tumor samples ex vivo results in upregulation of lncRNASAT1. The lncRNASAT1 is down-regulated in PCa tumor tissues compared to non-tumor tissues of same patients indicating a tumor suppressive function. Knockdown indicates that the lncRNASAT1 is crucial for SAL-induced cancer cell senescence and regulates LNCaP cell proliferation being an upstream factor for pAkt and for p15. Further, knockdown of lncRNASAT1 inhibits LNCaP cell proliferation by low androgen levels but enhances proliferation by SAL. This suggests that lncRNASAT1 serves as a tumor suppressor with SAL. Interestingly, immunoprecipitation of AR detected lncRNASAT1 as an AR interacting partner that regulates AR target gene expression. Thus, we identified a novel pathway of androgen signaling as the AR- lncRNASAT1- Akt- p15INK4b- axis to mediate SAL-induced cellular senescence.