Inhibition of Specificity Protein 1 Is Involved in Phloretin-Induced Suppression of Prostate Cancer.

Dan Kang,Qingyi Zhu,Ping Liu,Wenren Zuo,Qingxin Wu

doi:10.1155/2020/1358674

Abstract

Phloretin is a flavonoid existed in various plants and has been reported to possess anticarcinogenic activity. However, the anticancer mechanism of phloretin in prostate cancer (PCa) remains unclear. Here, our in vitro and in vivo experimental data demonstrate that phloretin inhibits the phosphorylation and the activation of EGFR and then inhibits its downstream PI3K/AKT and MEK/ERK1/2 pathways in PCa cells. Inhibition of these two pathways further decreases expression of Sp1 by inhibiting Sp1 gene transcription, induces degradation of Sp1 protein by inhibiting GSK3β phosphorylation, suppresses nucleolin-enhanced translation of Sp1 mRNA by inhibiting nucleolin phosphorylation, and directly inactivates transcription activity of Sp1. Inhibition of Sp1 subsequently decreases the expression of Sp3/4, VEGF, and Survivin and then upregulates apoptosis-related proteins and downregulates cell cycle-related proteins in PCa cells. Finally, phloretin treatment in PCa cells induces cell growth inhibition and apoptosis, suggesting that phloretin may be an effective therapy compound in the treatment of prostate cancer.

Highlights

Prostate cancer is a commonly diagnosed cancer and the fifth leading cause of cancer deaths in men in the world [1]
In exploring the molecular mechanism of phloretin-induced cell growth inhibition, cell cycle arrest, and apoptosis in prostate cancer (PCa) cells, we found that phloretin treatment substantially downregulated the autophosphorylation levels of EGFR at Y1173, but not the total protein level of EGFR (Figure 4(a)), suggesting the activity of EGFR was inhibited by phloretin
We reported that phloretin could inhibit the activation of EGFR and its downstream signal pathways, including the PI3K/AKT, MEK/ERK1/2, and GSK3β pathways

Summary

Introduction

Prostate cancer is a commonly diagnosed cancer and the fifth leading cause of cancer deaths in men in the world [1]. Phosphorylation of nucleolin mediated by VEGF (at Thr and Thr84) and EGFR (at Thr641/Thr707) plays a crucial role in binding to and enhancing the translation of target mRNAs [30, 31]. Phloretin treatment in PCa cells decreases the autophosphorylation level of EGFR and its activity and inhibits its downstream PI3K/AKT and MEK/ERK1/2 pathways. Inhibition of these two pathways subsequently suppresses Sp1 activity by decreasing the expression of Sp1 gene, enhancing the degradation of Sp1 protein, decreasing the translation of Sp1 mRNA, and reducing the DNAbinding of Sp1, and results in the downexpression of Sp1-targed Sp3/4, VEGF, and Survivin genes. The levels of Bax, cleaved Caspase-3/-8/-9, and cleaved PARP-1 are upregulated, while the levels of XIAP, Cyclin B1, and Bcl-2 are downregulated, and cell growth inhibition and apoptosis are induced by the treatment of phloretin in PCa cells in vitro and in vivo

Materials and Methods

Results

Phloretin Suppressed Tumor Growth and Induced

Discussion