Influence of pH on the Cytotoxic Activity of Inositol Hexakisphosphate (IP6) in Prostate Cancer

Objectives: In the present study, we investigated whether the pH of IP6 could influence its anti-tumoral activity in vitro. Methods: PC-3 cells were exposed to IP6 at pH 5, pH 7, and pH 12 and we evaluated the metabolic activity (WST-1 assay), cell proliferation (cell count), cell cycle distribution (FACS), and mitochondrial depolarization (JC-1 staining) in vitro. Results: Our results demonstrated that IP6 at pH 5 and pH 12 were more potent at lowering the metabolic activity of PC-3 cells than IP6 at pH 7. Treatment with IP6 at pH 12 also caused the greatest inhibition in cellular proliferation and accumulation of PC-3 cells in sub-G1. Finally, IP6 at pH 12 lead to a reduction in phospho-AKT and phospho-PDK1 and upregulated phospho-ERK. Conclusion: Together, our data strongly suggest that the pH of IP6 effectively modulates its anti-tumoral activity and should be reported in future studies

Ebp1 expression in benign and malignant prostate

<p>Abstract</p> <p>Background</p> <p>ErbB3-binding protein 1 (Ebp1) is a member of the <it>PA2G4 </it>family of proliferation-regulated proteins that is expressed in multiple malignant and non-malignant cells. ErbB3 and other members of the EGFR family have been implicated in cancer progression, it however remains unknown whether Ebp1 participate in prostate cancer progression <it>in vivo</it>. Therefore, the present study examines Ebp1 expression in cancerous and non-cancerous prostates tissues. Ebp1 expression was also correlated to known Ebp1 regulated proteins (Androgen receptor (AR), Cyclin D1 & ErbB3) and the proliferation marker Ki67. Furthermore we evaluated whether Ebp1 expression correlated with biochemical recurrence (BCR) following radical prostatectomy.</p> <p>Methods</p> <p>The expression of Ebp1, AR, Cyclin D1, ErbB3 and Ki67 were evaluated by immunohistochemistry using three separate tissue micro-arrays containing normal prostate tissues, non-cancerous tissue adjacent to the primary tumor, hormone-sensitive and hormone-refractory cancerous tissues. Multivariate COX regression analysis was performed with four clinical parameters in order to correlate Ebp1 expression with PCa progression.</p> <p>Results</p> <p>The expression of Ebp1 significantly increased with the progression from normal to hormone sensitive and to hormone refractory PCa. Furthermore, we observed strong correlation between Ebp1 expression and the nuclear expression of AR, Cyclin D1 and ErbB3 in both normal adjacent and cancer tissues. The expression of AR, Cyclin D1 and ErbB3 in normal adjacent tissues correlated with PSA relapse, whereas Ebp1 on its own did not significantly predict PSA relapse. Finally, in a multivariate analysis with a base clinical model (Gleason, Pre-op PSA, surgical margins and P-stage) we identified the multi-marker combination of Ebp1+/Cyclin D1- as an independent predictor of PSA relapse with a hazard ratio of 4.79.</p> <p>Conclusion</p> <p>Although not related to disease recurrence, this is the first <it>in vivo </it>study to report that Ebp1 expression correlates with PCa progression.</p

Intérêt de l’inspection visuelle à l’acide acétique et au soluté de Lugol avec colposcope dans le dépistage des lésions du col utérin au Gabon

Introduction: Au Gabon, le dépistage des lésions précancéreuses et cancéreuses du col de l'utérus n'est pas systématique. La vulgarisation de ce dépistage suppose l'utilisation d'un test efficace et adapté aux réalités locales. Méthodes: L'objectif de cette étude était de comparer les performances du frottis cervico-vaginal (FCV)  conventionnel et de l'inspection visuelle à l'acide acétique (IVA) et au soluté de  Lugol (IVL) couplée à la  colposcopie, dans la détection des lésions du col utérin au Gabon. Des tests IVA/IVL et FCV ont été effectués chez 309 femmes gabonaises âgées de 18 à 75 ans. Des biopsies ont été réalisées en cas de résultat positif. Résultats: 5 cancers épidermoïdes (1,6%) et 4 lésions précancéreuses (1,3%) ont été confirmées par   l'histologie. L'IVA/IVL a présenté une meilleure sensibilité (100%) que le FCV (89%). Toutefois, le FCV est  apparu plus spécifique (100% versus 92%). Avec une valeur prédictive (VP) négative de 100%, l'IVA/IVL a  permis d'exclure avec certitude la présence de cancer du col lorsque le résultat était négatif, contrairement au FCV (92%). L'IVA/IVL et le FCV ont présenté des VP positives respectivement de 90% et 100%. Conclusion: Cette étude montre que l'IVA/IVL avec colposcope couplée à l'histologie en cas de résultat  positif apparaît plus performante que le FCV.Key words: Col de l´utérus, lésions précancéreuses, cancer, IVA/IVL, FCV, Gabo

Expression of NRG1 and its receptors in human bladder cancer

BACKGROUND: Therapies targeting ERBB2 have shown success in the clinic. However, response is not determined solely by expression of ERBB2. Levels of ERBB3, its preferred heterodimerisation partner and ERBB ligands may also have a role. METHODS: We measured NRG1 expression by real-time quantitative RT–PCR and ERBB receptors by western blotting and immunohistochemistry in bladder tumours and cell lines. RESULTS: NRG1a and NRG1b showed significant coordinate expression. NRG1b was upregulated in 78 % of cell lines. In tumours, there was a greater range of expression with a trend towards increased NRG1a with higher stage and grade. Increased expression o

Expression and localisation of Akt-1, Akt-2 and Akt-3 correlate with clinical outcome of prostate cancer patients

We investigated the correlation between the expression and localisation of Akt-1, Akt-2, Akt-3, phospho-Akt proteins and the clinicopathological parameters in 63 prostate cancer specimens. More than 60% of cancerous tissues overexpressed Akt-1, Akt-2 or Akt-3. Cytoplasmic Akt-1 expression was correlated with a higher risk of postoperative prostate-specific antigen (PSA) recurrence and shorter PSA recurrence interval. Cytoplasmic Akt-2 did not show any significant correlation with clinicopathological parameters predicting outcomes. Cytoplasmic Akt-3 was associated with hormone-refractory disease progression and extracapsular invasion. Nuclear Akt-1 and Akt-2 expression were correlated with favourable outcome parameters such as absence of lymph node and perineural invasion. Kaplan–Meier analysis and Cox regression model also showed that Akt-1 and Akt-2, but not Akt-3 or phospho-Akt was associated with a significantly higher risk of PSA recurrence. In contrast, nuclear Akt-1 was significantly associated with a lower risk of PSA recurrence. Multivariate analysis revealed that clinical stage, Gleason score and the combined cytoplasmic nuclear Akt-1 marker in cancerous tissues were significant independent prognostic factors of PSA recurrence. This is the first report demonstrating in patients with prostate cancer and the particular role of Akt-1 isoform expression as a prognostic marker depending of its localisation

Androgen-Regulated Expression of Arginase 1, Arginase 2 and Interleukin-8 in Human Prostate Cancer

BACKGROUND: Prostate cancer (PCa) is the most frequently diagnosed cancer in North American men. Androgen-deprivation therapy (ADT) accentuates the infiltration of immune cells within the prostate. However, the immunosuppressive pathways regulated by androgens in PCa are not well characterized. Arginase 2 (ARG2) expression by PCa cells leads to a reduced activation of tumor-specific T cells. Our hypothesis was that androgens could regulate the expression of ARG2 by PCa cells. METHODOLOGY/PRINCIPAL FINDINGS: In this report, we demonstrate that both ARG1 and ARG2 are expressed by hormone-sensitive (HS) and hormone-refractory (HR) PCa cell lines, with the LNCaP cells having the highest arginase activity. In prostate tissue samples, ARG2 was more expressed in normal and non-malignant prostatic tissues compared to tumor tissues. Following androgen stimulation of LNCaP cells with 10 nM R1881, both ARG1 and ARG2 were overexpressed. The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. This observation was correlated in vivo in patients by immunohistochemistry. Patients treated by ADT prior to surgery had lower ARG2 expression in both non-malignant and malignant tissues. Furthermore, ARG1 and ARG2 were enzymatically active and their decreased expression by siRNA resulted in reduced overall arginase activity and l-arginine metabolism. The decreased ARG1 and ARG2 expression also translated with diminished LNCaP cells cell growth and increased PBMC activation following exposure to LNCaP cells conditioned media. Finally, we found that interleukin-8 (IL-8) was also upregulated following androgen stimulation and that it directly increased the expression of ARG1 and ARG2 in the absence of androgens. CONCLUSION/SIGNIFICANCE: Our data provides the first detailed in vitro and in vivo account of an androgen-regulated immunosuppressive pathway in human PCa through the expression of ARG1, ARG2 and IL-8

The Receptor Tyrosine Kinase FGFR4 Negatively Regulates NF-kappaB Signaling

NFκB signaling is of paramount importance in the regulation of apoptosis, proliferation, and inflammatory responses during human development and homeostasis, as well as in many human cancers. Receptor Tyrosine Kinases (RTKs), including the Fibroblast Growth Factor Receptors (FGFRs) are also important in development and disease. However, a direct relationship between growth factor signaling pathways and NFκB activation has not been previously described, although FGFs have been known to antagonize TNFα-induced apoptosis. assays. FGF19 stimulation of endogenous FGFR4 in TNFα-treated DU145 prostate cancer cells also leads to a decrease in IKKβ activity, concomitant reduction in NFκB nuclear localization, and reduced apoptosis. Microarray analysis demonstrates that FGF19 + TNFα treatment of DU145 cells, in comparison with TNFα alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NFκB signaling.These results identify a compelling link between FGFR4 signaling and the NFκB pathway, and reveal that FGFR4 activation leads to a negative effect on NFκB signaling including an inhibitory effect on proapoptotic signaling. We anticipate that this interaction between an RTK and a component of NFκB signaling will not be limited to FGFR4 alone