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The Rac1/Cdc42 regulator CdGAP promotes prostate cancer metastasis by regulating epithelial-to-mesenchymal transition, cell cycle progression, and apoptosis

ABSTRACT: The high mortality of prostate cancer (PCa) patients is primarily due to metastasis, which can be associated with castration-resistant PCa. Therefore, understanding the mechanisms controlling metastatic processes remains essential to improve the success of targeted therapies. The Rac1/Cdc42 regulator CdGAP (Cdc42 GTPase-activating protein) has been implicated in fundamental cellular processes involved during cancer progression. Here, we demonstrate that elevated CdGAP expression is associated with early biochemical relapse (BCR) and bone metastasis in PCa patients. Furthermore, gene expression analysis of CdGAP in PCa data sets revealed a positive association between high CdGAP expression and early BCR. CdGAP protein and mRNA levels were elevated in PC-3 cells with high metastatic potential compared to low levels of CdGAP in the androgen receptor positive LNCaP cell line. Knockdown of CdGAP in PC-3 cells reduced cell motility, invasion, proliferation and colony-formation ability while inducing an increase in cell apoptosis. Conversely, overexpression of CdGAP in DU-145 cells increased cell migration and invasion. Using global gene expression approaches we found that CdGAP regulates the expression of genes involved in EMT, apoptosis and cell cycle progression. Subcutaneous injection of CdGAP-depleted PC-3 cells into mice showed a delayed tumor initiation and attenuated tumor growth. Orthotopic prostate injection of CdGAP-depleted PC-3 cells reduced cancer metastasis to kidneys, bones, and testis. Collectively, these findings support a pro-oncogenic role of CdGAP in prostate tumorigenesis and unveil CdGAP as a novel biomarker and potential target for prostate cancer treatments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160399 | GEO | 2021/08/12

REPOSITORIES: GEO

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Project description:Background: Aldo-keto reductase (AKR) 1C family member 3 (AKR1C3), one of four identified human AKR enzymes, catalyzes steroid, prostaglandin, and xenobiotic metabolism. In the prostate, AKR1C3 is up-regulated in localized and advanced prostate adenocarcinoma, and is associated with prostate cancer (PCa) aggressiveness. Here we provide initial evidence for potential roles of AKR1C3 in PCa progression. Methods: Spatial distribution of AKR1C3 was analyzed using immunohistochemical staining in prostate adenocarcinoma tissue array. Human PCa PC-3 cells were stably transfected with AKR1C3 cDNA to establish PC3-AKR1C3 transfectants. Microarray and bioinformatics analyses were performed to identify pathways that are activated by elevated AKR1C3 expression in PCa cells. Functional confirmation of microarray and bioinformatics results was performed by immunoblot analysis and an in vitro Matrigel angiogenesis assay. Results: Elevated AKR1C3 expression was specifically limited to human prostate adenocarcinoma. Microarray and bioinformatics analysis suggested that elevated AKR1C3 expression in PC-3 cells modulates estradiol and androgen metabolism and activates insulin growth factor (IGF)-1 and Akt signaling pathways. Immunoblots confirmed that phosphorylated levels of IGF-1 receptor (IGF-1R) and Akt are significantly up-regulated in PC3-AKR1C3 as compared to mock transfectants. PC3-AKR1C3 transfectants promoted endothelial cell tube formation in Matrigel as compared to parental PC-3 cells and mock transfectants. Conclusion: Microarray and bioinformatics data followed by biological analyses suggest that elevated AKR1C3 expression in PC-3 cells promotes PCa angiogenesis and aggressiveness. These results suggest AKR1C3 can promote the aggressiveness of PCa through modulating estrogen and androgen metabolism with subsequent activation of growth factor IGF-1 and cytoplasmic Akt signaling pathways. Total RNA from mock- and ACR1C3 transfected PC-3 cells was isolated, with 2 or 3 biological replicates each. Gene expression data from AKR1C3 transfected PC-3 cells were compared with mock-transfected data.

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The Rac1/Cdc42 regulator CdGAP promotes prostate cancer metastasis by regulating epithelial-to-mesenchymal transition, cell cycle progression, and apoptosis

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