PI3K pathway and Bcl-2 family. Clinicopathological features in prostate cancer

Torrealba, Norelia; Rodríguez-Berriguete, Gonzalo; Fraile, Benito; Olmedilla, Gabriel; Martínez-Onsurbe, Pilar; Sánchez‐Chapado, Manuel; Paniagua, Ricardo; Royuela, Mar

doi:10.1080/13685538.2018.1424130

Cited by 23 publications

(10 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, AKT was also identified in the present study. Indeed up to 49% of PC tumors are thought to have aberrant PI3K signaling, making it the 2nd most frequently altered pathway in PC [68–70]. However, PI3K monotherapies for PC are ineffective, most likely due to their lack of specificity and complex signaling feedback mechanisms [68, 69, 71–74].…”

Section: Discussionmentioning

confidence: 99%

Bloom Syndrome Protein Activates AKT and PRAS40 in Prostate Cancer Cells

Chen

Zhao

2019

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Purpose. Prostate cancer (PC) is a common malignant tumor and a leading cause of cancer-related death in men worldwide. In order to design new therapeutic interventions for PC, an understanding of the molecular events underlying PC tumorigenesis is required. Bloom syndrome protein (BLM) is a RecQ-like helicase, which helps maintain genetic stability. BLM dysfunction has been implicated in tumor development, most recently during PC tumorigenesis. However, the molecular basis for BLM-induced PC progression remains poorly characterized. In this study, we investigated whether BLM modulates the phosphorylation of an array of prooncogenic signaling pathways to promote PC progression. Methods. We analyzed differentially expressed proteins (DEPs) using iTRAQ technology. Site-directed knockout of BLM in PC-3 prostate cancer cells was performed using CRISPR/Cas9-mediated homologous recombination gene editing to confirm the effects of BLM on DEPs. PathScan® Antibody Array Kits were used to analyze the phosphorylation of nodal proteins in PC tissue. Immunohistochemistry and automated western blot (WES) analyses were used to validate these findings. Results. We found that silencing BLM in PC-3 cells significantly reduced their proliferative capacity. In addition, BLM downregulation significantly reduced levels of phosphorylated protein kinase B (AKT (Ser473)) and proline-rich AKT substrate of 40 kDa (PRAS40 (Thr246)), and this was accompanied by enhanced ROS (reactive oxygen species) levels. In addition, we found that AKT and PRAS40 inhibition reduced BLM, increased ROS levels, and induced PC cell apoptosis. Conclusions. We demonstrated that BLM activates AKT and PRAS40 to promote PC cell proliferation and survival. We further propose that ROS act in concert with BLM to facilitate PC oncogenesis, potentially via further enhancing AKT signaling and downregulating PTEN expression. Importantly, inhibiting the BLM-AKT-PRAS40 axis induced PC cell apoptosis. Thus, we highlight new avenues for novel anti-PC treatments.

show abstract

Section: Discussionmentioning

confidence: 99%

Bloom Syndrome Protein Activates AKT and PRAS40 in Prostate Cancer Cells

Chen

Zhao

2019

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

show abstract

“…Bcl-2, a well-known apoptosis suppressor gene, is involved in the progression of multiple tumors. 22 , 23 Studies have reported that many miRNAs can regulate the expression of Bcl-2 . 24 However, the mechanism through which Bcl-2 participates in SCLC biology under the regulation of miR-216a-5p remained obscure.…”

Section: Discussionmentioning

confidence: 99%

miR-216a-5p inhibits malignant progression in small cell lung cancer: involvement of the Bcl-2 family proteins

Sun

Wang³

et al. 2018

CMAR

View full text Add to dashboard Cite

ObjectivemicroRNAs are regulatory molecules regarded as important in the pathogenesis of different types of tumors. microRNA-216a (miR-216a-5p) has been identified as a tumor suppressor in multiple malignancies. However, the role of miR-216a-5p in the pathogenesis of small cell lung cancer (SCLC) remains obscure. The objective of this study was to investigate the role of the miR-216a-5p/Bcl-2 axis in SCLC pathogenesis.Materials and methodsAll the experimental methods used were as follows: microarray analysis, cell culture, transient, and stable gene transfection; real-time fluorescence PCR; Western blot; flow cytometry for cell cycle analysis; in vitro proliferation assay; in vitro wound healing experiment; in vivo xenograft model in nude mice; and dual luciferase reporter assay. All statistical analyses were carried out using GraphPad Prism 7 software. Statistical significance was analyzed by Student’s t-test or one-way ANOVA. P <0.05 (typically compared with the negative control group) was considered as significant and is marked with an asterisk in the figures.ResultsIn this study, we observed that miR-216a-5p is downregulated in SCLC cell lines compared to that in the normal human bronchial epithelial cell line 16-HBE. In vitro and in vivo experiments demonstrate that upregulation of miR-216a-5p significantly decreased cell growth and migration and its downregulation increased SCLC cell proliferation and migration and influenced the cell cycle. Using bioinformatics analyses, we predicted that the important antiapoptotic gene Bcl-2 is targeted by miR-216a-5p, and we identified a functional miR-216a-5p binding site in the 3′-UTR of Bcl-2 using luciferase reporter assay. Furthermore, we determined that suppression of miR-216a-5p modulated the expression of Bcl-2, Bax, and Bad proteins (Bcl-2 family proteins), while Bcl-2 knockdown abrogated the effect of miR-216a-5p downregulation on cell proliferation, cell migration, and the cell cycle.ConclusionTaken together, these findings suggest that miR-216a-5p regulates SCLC biology via Bcl-2 family proteins. Therefore, our study highlights the role of the miR-216a-5p/Bcl-2 axis in SCLC pathogenesis.

show abstract

“…It results suggest a role for prostatic expression of PI3K has prognostic markers for PC. Also, PI3K/AKT/mTOR and Bcl-2 family are becoming an important therapeutic target and predictive biomarkers of onset and progression of PCa [20]. The literature study has revealed a set of critical genes, which can provide etiologic clues as to enzalutamideresistant prostate cancer and guide novel therapeutic approaches [21].…”

Section: Introductionmentioning

confidence: 99%