ESTAT3 Inhibitor AG-490 Inhibits the Growth of Prostate Cancer by miR-503-5p Both In Vivo and In Vitro

Abstract

Objective: To explore the effect and the related mechanism of STAT3 inhibitor AG-490 on inhibiting the proliferation of prostate cancer cells. Methods: PC3 cells and DU145 cells were cultured stably and treated with AG-490 to detect the changes in the activity of PC3 cells and DU145 cells. Thirty 6-8 weeks male BALB/c nude mouse were randomly divided into a control group, a DMSO group, and an AG-490 group to detect differences in various indexes . Results: The overexpression of miR-503-5p depends on the activation of STAT3. After treatment with AG-490, The proliferation and invasion of PC3 cells and DU145 cells and the expression of miR-503-5p were all reduced. Luciferase reporter assay demonstrated that the target proteins of miR-503-5p include PDCD4, TIMP-3, and PTEN. After treatment with AG-490, the expression of PDCD4, TIMP-3, and PTEN in cells was significantly up-regulated. IL-6-induced overexpression of miR-503-5p and restored the expression of STAT3, demonstrating the correlation between STAT3 and miR-503-5p. AG-490 can inhibit tumor growth and induce tumor cell apoptosis in the PC3 BALB/c nude mouse xenograft model. Western blotting and immunohistochemical staining showed that the expression levels of STAT3, Ki67, Bcl-2 and MMP-2 in the AG-490 group were significantly reduced, and the expression of PDCD4, TIMP-3 and PTEN increased. Conclusion: AG-490 can inhibit the growth of prostate cancer cells in a miR-503-5p-dependent manner by targeting STAT3. AG-490 is expected to become a new candidate drug for the treatment of prostate cancer.

ALDH3A2, ODF2, QSOX2, and MicroRNA-503-5p Expression to Forecast Recurrence in TMPRSS2-ERG-Positive Prostate Cancer

“…It was notable that the two identified miRNAs have previously been described in PCa and in other cancers. A recent study demonstrated that a change in the level of expression of the miRNA hsa-miR-503-5p is associated with the degree of differentiation of tumor cells in PCa [ 22 ]. Upregulation of hsa-miR-503-5p in BCR cases may be associated with a decrease in the expression of PTEN , TIMP3, and PDCD4 and activation of the AKT signaling pathway [ 22 ].…”

“…A recent study demonstrated that a change in the level of expression of the miRNA hsa-miR-503-5p is associated with the degree of differentiation of tumor cells in PCa [ 22 ]. Upregulation of hsa-miR-503-5p in BCR cases may be associated with a decrease in the expression of PTEN , TIMP3, and PDCD4 and activation of the AKT signaling pathway [ 22 ]. TIMP3 is an inhibitor of MMP , and, when it is suppressed, MMP2 is activated, this being involved in the destruction of the extracellular matrix, which, therefore, probably promotes cell motility, inducing migration and invasion [ 22 , 23 ].…”

“…Upregulation of hsa-miR-503-5p in BCR cases may be associated with a decrease in the expression of PTEN , TIMP3, and PDCD4 and activation of the AKT signaling pathway [ 22 ]. TIMP3 is an inhibitor of MMP , and, when it is suppressed, MMP2 is activated, this being involved in the destruction of the extracellular matrix, which, therefore, probably promotes cell motility, inducing migration and invasion [ 22 , 23 ]. Moreover, we found upregulation of hsa-miR-200b-3p, while a recent study detected that hsa-miR-200b-3p knockdown inhibits PCa cell proliferation and promotes cell apoptosis [ 24 ], although the mechanisms of this effect are not yet known.…”

MiR-183-5p Promotes Migration and Invasion of Prostate Cancer by Targeting TET1

“…A transwell chamber with an 8-µm pore size polycarbonate membrane (Corning, NY) was used to evaluate cell migration. After 48h of transfection, the PCa cells were resuspended with basic medium and seeded into the upper chamber (2×10 4 for PC-3 cells and 5×10 4 for LNCaP cells), while culture medium containing 15% FBS was added to the lower chamber. After incubation for 48 h at 37°C, the medium was removed from the upper chamber, and non-migrated cells were scraped off with a cotton swab.…”

“…Thus, in-depth understanding of the mechanism of metastatic PCa will help us intervene and treat of PCa patients better. Previous studies have con rmed that the malignant progress of PCa is a multi-step and multi-stage progress, which is involved with the dysregulation of multiple molecules, including miRNAs [4][5][6].…”