Aspirin Inhibits IKK-ß-mediated Prostate Cancer Cell Invasion by Targeting Matrix Metalloproteinase-9 and Urokinase-Type Plasminogen Activator.

BACKGROUND/AIMS: Aspirin has been demonstrated to possess potent chemopreventive and anticancer effects on prostate cancer. However, the more detailed molecular mechanisms of aspirin to suppress prostate cancer cell invasion have not been clearly elucidated. METHODS: Transwell assays were performed to evaluate the effects of aspirin on cell invasion. Matrix metalloproteinases (MMPs) and serine proteinases activities in cell media were examined by gelatin zymography and ELISA. In addition, inhibitor of κB (IκB) kinase-ß (IKK-ß) phosphorylation and IKK-ß kinase activity were measured to assess the effects of aspirin on IKK-ß activation. RESULTS: We found that aspirin suppressed the invasion and attachment in human prostate cancer cells. Aspirin treatment significantly resulted in reduction of matrix metalloproteinase-9 (MMP-9) and upregulation of tissue inhibitors of metalloproteinase-1 (TIMP-1) activity, which are the proteolytic enzymes contributing to the degradation of extracellular matrix and basement membrane in cell invasion and metastasis. Our data further showed that aspirin was able to inhibit both urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) expression in the cells. In addition, aspirin treatment caused a strong decrease in nuclear factor-kappa B (NF-κB) activation, inhibitor of κB (IκB)-α phosphorylation together with translocation of NF-κB p65 to nucleus and IκB kinase (IKK)- ß activation. Moreover, the inhibitory effects of aspirin on cell invasion were reversed by IKK-ß overexpression, while the IKK inhibitor sensitizes the anti-invasive effect of aspirin in prostate cancer cells. CONCLUSION: The present research concluded that aspirin suppressed prostate cancer cell invasion by reducing MMP-9 activity and uPA expression through decreasing of IKK-ß-mediated NF-κB activation, indicating that the ability of aspirin to inhibit cell invasion might be useful in the chemoprevention of metastatic prostate cancer.

Increased expression of microRNA-93 correlates with progression and prognosis of prostate cancer.

MicroRNA-93 (miR-93) has been found to be up-regulated in multiple malignancies. miR-93 might promote the proliferation and invasion of prostate cancer cell. In the present study, we aimed to investigate the expression level of miR-93 in prostate cancer tissues and its clinical and prognostic value in patients with prostate cancer.A total of 103 paired prostate cancer tissues and adjacent normal tissues were obtained from male patients who underwent surgical treatment in the department of urology, Huizhou Third People's Hospital, Guangzhou Medical University between July 2014 and March 2018. The correlation between prostate cancer characteristics and miR-93 expression was examined by chi-square test. Patient survival was evaluated using the Kaplan-Meier method and compared using log-rank test. Univariate and multivariate Cox regression analyses were performed for survival data.Compared to noncancerous prostate tissues, the expression levels of miR-93 in prostate cancer tissues were significantly increased (P < .001). High level of miR-93 expression was significantly correlated with Gleason score (P = .018), lymph node involvement (P = .026), bone metastasis (P < .001), and Tumor Node Metastasis (TNM) stage (P < .001). The 5-year overall survival rate in the high expression group was lower than that in the low expression group (log-rank test, P = .031). Multivariate Cox regression analysis showed that miR-93 expression level (HR = 2.181, 95% CI: 1.092-6.829, P = .028) was an independent factor in predicting the overall survival of prostate cancer patients.The present study demonstrated that increased expression of miR-93 correlates with progression and prognosis of prostate cancer. These fndings suggest miR-93 may serve as a novel target for prostate cancer prognosis and therapy.

ABL-N may induce apoptosis of human prostate cancer cells through suppression of KLF5, ICAM-1 and Stat5b, and upregulation of Bax/Bcl-2 ratio: An in vitro and in vivo study.

Identification of novel botanicals that can selectively induce apoptosis and arrest growth of cancer cells without producing cytotoxic effects is highly appreciable for cancer therapy. The present study aimed to investigate the possibility of acetylbritannilactone (ABL) derivative 5-(5-(ethylperoxy)pentan-2-yl)-6-methyl-3-methylene-2-oxo-2,3,3a,4,7,7a­hexahydroben-zofuran-4-yl2-(6-methoxynaphthalen-2-yl) propanoate (ABL-N) as a therapeutic agent in human prostate cancer and potential mechanisms. Human prostate cancer cells were treated with ABL-N of different concentrations (0, 5, 10, 20, 30 and 40 µmol/l). Cell viability, migration and apoptosis were determined. Activities of caspases were assayed, as well as protein expression of cancer­related proteins KLF5, Stat5b and ICAM-1 in PC3 cells. The therapeutic effect of ABL-N was further evaluated in our tumor xenografts. ABL-N inhibited growth of prostate cancer cells in a dose-dependent manner, without obvious effect on normal human prostate epithelial PrEC cells. ABL-N administration induced apoptosis of PC3 cells in a dose-dependent manner, along with the enhanced activity of caspases and increased Bax/Bcl-2 ratio. Expression of KLF5, Stat5b and ICAM-1 was significantly downregulated in PC3 cells. Our in vivo study further confirmed that ABL-N significantly inhibited the tumor growth of PC3 cells in the xenograft mouse model. ABL-N induces apoptosis of prostate cancer cells through activation of caspases, increasing the ratio of Bax/Bcl-2, as well as suppression of KLF5, Stat5b and ICAM-1 expressions. The present study indicated that ABL-N may be a potential therapeutic drug for human prostate cancer, and our data supported further studies to explore the therapeutic potential of ABL-N in other types of human cancer.