Bloom Syndrome Protein Activates AKT and PRAS40 in Prostate Cancer Cells

Overview

Journal Oxid Med Cell Longev

Publisher Wiley

Specialties Cell Biology
Endocrinology

Date 2019 Jun 19

PMID 31210839

Citations 16

Authors

Kun Chen

Houqiang Xu

Jiafu Zhao

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Synergistic effects of bloom helicase (BLM) inhibitor AO/854 with cisplatin in prostate cancer.

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Targeting mRNA-coding genes in prostate cancer using CRISPR/Cas9 technology with a special focus on androgen receptor signaling.

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Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of functions.

Xu W, Liu L, Cui Z, Li M, Ni J, Huang N Open Med (Wars). 2023; 18(1):20230715.

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BLM promotes malignancy in PCa by inducing KRAS expression and RhoA suppression via its interaction with HDGF and activation of MAPK/ERK pathway.

Guo Y, Xu H, Huang M, Ruan Y J Cell Commun Signal. 2022; 17(3):757-772.

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Discovery of a Novel Bloom's Syndrome Protein (BLM) Inhibitor Suppressing Growth and Metastasis of Prostate Cancer.

Ma X, Xu H, Zhao J, Ruan Y, Chen B Int J Mol Sci. 2022; 23(23).

PMID: 36499126 PMC: 9736344. DOI: 10.3390/ijms232314798.

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