Bloom Syndrome Protein Activates AKT and PRAS40 in Prostate Cancer Cells

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.

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Statins induce cell apoptosis through a modulation of AKT/FOXO1 pathway in prostate cancer cells

Cancer Management and Research ◽

10.2147/cmar.s212643 ◽

2019 ◽

Vol Volume 11 ◽

pp. 7231-7242 ◽

Cited By ~ 5

Author(s):

Jun-Li Deng ◽

Rui Zhang ◽

Ying Zeng ◽

Yuan-Shan Zhu ◽

Guo Wang

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cell Apoptosis ◽

Prostate Cancer Cells ◽

Induce Cell Apoptosis

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794 MICRORNA-204 PROMOTES CELL APOPTOSIS BY TARGETING TO BCL-2 IN BLADDER AND PROSTATE CANCER CELLS

The Journal of Urology ◽

10.1016/j.juro.2013.02.358 ◽

2013 ◽

Vol 189 (4S) ◽

Author(s):

Thomas Hwang ◽

Yi-Chia Lin ◽

Te-Fu Tsai ◽

Hung-En Chen ◽

Kuang-Yu Chou ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cell Apoptosis ◽

Prostate Cancer Cells

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Gambogic Acid Induces Cell Apoptosis and Inhibits MAPK Pathway in PTEN−/−/p53−/− Prostate Cancer Cells In Vitro and Ex Vivo

Chinese Journal of Integrative Medicine ◽

10.1007/s11655-017-2410-3 ◽

2017 ◽

Vol 24 (2) ◽

pp. 109-116 ◽

Cited By ~ 5

Author(s):

Hong Pan ◽

Li-yuan Lu ◽

Xue-qian Wang ◽

Bin-xue Li ◽

Kathleen Kelly ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cell Apoptosis ◽

Ex Vivo ◽

Mapk Pathway ◽

Gambogic Acid ◽

Prostate Cancer Cells

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KLF9, a transcription factor induced in flutamide-caused cell apoptosis, inhibits AKT activation and suppresses tumor growth of prostate cancer cells

The Prostate ◽

10.1002/pros.22812 ◽

2014 ◽

Vol 74 (9) ◽

pp. 946-958 ◽

Cited By ~ 28

Author(s):

Pengliang Shen ◽

Jiabin Sun ◽

Guiqin Xu ◽

Li Zhang ◽

Zhaojuan Yang ◽

...

Keyword(s):

Prostate Cancer ◽

Transcription Factor ◽

Tumor Growth ◽

Cancer Cells ◽

Cell Apoptosis ◽

Prostate Cancer Cells ◽

Akt Activation

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Androgen Receptor Signaling Regulates the Transcriptome of Prostate Cancer Cells by Modulating Global Alternative Splicing

10.1101/828707 ◽

2019 ◽

Author(s):

Kalpit Shah ◽

Teresa Gagliano ◽

Lisa Garland ◽

Timothy O’Hanlon ◽

Daria Bortolotti ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Alternative Splicing ◽

Cancer Cells ◽

Cancer Patients ◽

Treatment Resistance ◽

Progression Free Survival ◽

Therapeutic Interventions ◽

Prostate Cancer Cells

AbstractAndrogen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen-deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line anti-androgen therapies, including bicalutamide (CASODEX®) and enzalutamide (XTANDI®). However, the progression-free survival rate for the CRPC patients on anti-androgen therapies is only 8 to 19 months. Hence, there is a need to understand the mechanisms underlying CRPC progression and eventual treatment resistance. Here, we have leveraged next-generation sequencing and newly developed analytical methodologies to evaluate the role of AR-signaling in regulating the transcriptome of prostate cancer cells. The genomic and pharmacologic stimulation- and inhibition-of AR activity demonstrates that AR regulates alternative splicing within cancer-relevant genes. Furthermore, by integrating transcriptomic data from in vitro experiments and in prostate cancer patients, we found that a significant number of AR-regulated splicing events are associated with tumor progression. For example, we found evidence for an inadvertent AR-antagonist mediated switch in IDH1 and PL2G2A isoform expression, which is associated with a decrease in overall survival of patients. Mechanistically, we discovered that the epithelial-specific splicing regulators (ESRP1 and ESRP2), flank many AR-regulated alternatively spliced exons. And, using 2D-invasion assays, we show that the inhibition of ESRPs can suppress AR-antagonist driven tumor invasion. In conclusion, until now, AR signaling has been primarily thought to modulate transcriptome of prostate epithelial cells by inducing or suppressing gene expression. Our work provides evidence for a new mechanism by which AR alters the transcriptome of prostate cancer cells by modulating alternative splicing. As such, our work has important implications for CRPC progression and development of resistance to treatment with bicalutamide and enzalutamide.

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Flavokawain A inhibits prostate cancer cells by inducing cell cycle arrest and cell apoptosis and regulating the glutamine metabolism pathway

Journal of Pharmaceutical and Biomedical Analysis ◽

10.1016/j.jpba.2020.113288 ◽

2020 ◽

Vol 186 ◽

pp. 113288 ◽

Cited By ~ 1

Author(s):

Kaili Wang ◽

Weijie Zhang ◽

Zihan Wang ◽

Ming Gao ◽

Xinying Wang ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Cell Apoptosis ◽

Glutamine Metabolism ◽

Prostate Cancer Cells ◽

Metabolism Pathway ◽

Cycle Arrest

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Abstract 4075: Tolfenamic Acid Inhibits Prostate Cancer Cells Growth and Tumor Development in Orthotopic Mice

10.1158/1538-7445.am10-4075 ◽

2010 ◽

Author(s):

Riyaz B. Mahammad ◽

Rafael Madero-Visbal ◽

Cheryl H. Baker ◽

Jimmie Colon ◽

Stephen Safe ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Tumor Development ◽

Tolfenamic Acid ◽

Prostate Cancer Cells

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Upregulation of Circular RNA Itchy E3 Ubiquitin Protein Ligase Inhibits Cell Proliferation and Promotes Cell Apoptosis Through Targeting MiR-197 in Prostate Cancer

Technology in Cancer Research & Treatment ◽

10.1177/1533033819886867 ◽

2019 ◽

Vol 18 ◽

pp. 153303381988686 ◽

Cited By ~ 1

Author(s):

Yuan Yuan ◽

Xiaogang Chen ◽

Enying Huang

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Western Blot ◽

Cancer Cells ◽

Cell Apoptosis ◽

Circular Rna ◽

Micro Rna ◽

Prostate Cancer Cells ◽

Ubiquitin Protein Ligase ◽

Proliferation And Apoptosis

Objective: This study aimed to investigate the effect of circular RNA itchy E3 ubiquitin protein ligase on cell proliferation and apoptosis and to explore its target micro-RNAs in prostate cancer cells. Methods: Circular RNA itchy E3 ubiquitin protein ligase expression in human prostate cancer cells and normal prostate epithelial cells was determined by real time-quantitative polymerase chain reaction assay. Circular RNA itchy E3 ubiquitin protein ligase overexpression plasmids (circular RNA itchy E3 ubiquitin protein ligase(+) group and control overexpression plasmids group were transfected with PC-3 cells. Rescue experiment was performed by transfection of circular RNA itchy E3 ubiquitin protein ligase overexpression and micro-197 overexpression plasmids (circular RNA itchy E3 ubiquitin protein ligase overexpression plasmids/micro RNA (+) group) into PC-3 cells. Cell Counting Kit-8 and annexin V/propidium iodide assays were conducted to evaluate cell proliferation and apoptosis, respectively. Western blot was performed to determine the expressions of apoptotic-related markers. Results: Circular RNA itchy E3 ubiquitin protein ligase expression was decreased in DU 145, 22RV1, VCaP, and PC-3 cells compared to RWPE cells. In PC-3 cells, cell proliferation rate was reduced in circular RNA itchy E3 ubiquitin protein ligase overexpression plasmids group compared to control overexpression plasmids group at 48 hours and 72 hours. Cell apoptosis rate was elevated in circular RNA itchy E3 ubiquitin protein ligase overexpression plasmids group compared to control overexpression plasmids group at 48 hours, and Western blot showed the similar results. Micro RNA-197 but not micro RNA-31 or micro RNA-432 was the target micro-RNA of circular RNA itchy E3 ubiquitin protein ligase. In rescue experiments, cell proliferation rate was elevated, but apoptosis rate was reduced in circular RNA itchy E3 ubiquitin protein ligase overexpression plasmids/micro RNA (+) group compared to circular RNA itchy E3 ubiquitin protein ligase overexpression plasmids group, indicating that circular RNA itchy E3 ubiquitin protein ligase upregulation inhibited cell proliferation but promoted apoptosis through downregulating micro RNA-197. Conclusion: Circular RNA itchy E3 ubiquitin protein ligase upregulation suppresses cell proliferation but promotes apoptosis through targeting micro RNA-197 in prostate cancer. Our study may provide a new insight for the treatment of prostate cancer.

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