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

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.

Phloretin inhibits glucose transport and reduces inflammation in human retinal pigment epithelial cells

“…Further studies will be necessary to fully elucidate the pathways regulated by phloretin and how it exerts its anti-inflammatory effects on IL-6. Phloretin-mediated inhibition of VEGF might involve the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, but this, too, will need further study to confirm [38,39]. Furthermore, in vitro studies, while an important first step in the study of molecular responses and pathways, can only provide a limited view into the complex mechanisms that underlie human disease.…”

Phloretin in Benign Prostate Hyperplasia and Prostate Cancer: A Contemporary Systematic Review

“…The anti-tumoral effect of antioxidants in prostate cells with normal prostate-specific antigen (PSA) would be reversed into pro-tumoral effect in prostate cells with high PSA [ 75 , 76 , 77 ], which was the most common for PCa. Another mechanism of treatment effect of phloretin in PC3 cell line was that it could efficiently induce apoptosis [ 13 ]. In the concentration of 100 μM, they also found that anti-apoptotic proteins, such as Bcl-2, were decreased and pro-apoptotic proteins, such as Bax and caspase-3, were increased [ 13 ].…”

“…Another mechanism of treatment effect of phloretin in PC3 cell line was that it could efficiently induce apoptosis [ 13 ]. In the concentration of 100 μM, they also found that anti-apoptotic proteins, such as Bcl-2, were decreased and pro-apoptotic proteins, such as Bax and caspase-3, were increased [ 13 ].…”

“…Contrary to PC3 and DU145 cell lines, it appears to be androgen sensitive. By inducing apoptosis, phloretin could offer its anti-tumoral effect in LNCaP cell lines [ 13 ]. Moreover, by inhibiting MEK/ERK1/2 pathways, Cox-2 expression could be downregulated in PCa [ 13 ], since the Cox-2 mediated-NF-κB pathway was related to the survival and migration of PCa cells [ 42 , 43 , 44 ], which was also effective in androgen-independent PCa.…”

Phloretin Ameliorates Testosterone-Induced Benign Prostatic Hyperplasia in Rats by Regulating the Inflammatory Response, Oxidative Stress and Apoptosis

“…Suppressing the former could interrupt the three-hit process and decrease APC in the prostate, whereas suppressing the latter could downregulate OS in the prostate. Moreover, the ability of phloretin to induce apoptosis, which can attenuate the development of prostate cancer, was also researched [ 11 ]. This makes phloretin a possible and attractive derivative to prevent BPH.…”