Isorhapontigenin induced cell growth inhibition and apoptosis by targeting EGFR‐related pathways in prostate cancer

Abstract

Isorhapontigenin (ISO), a naturally phytopolyphenol compound existing in Chinese herb, apples, and various vegetables, has attracted extensive interest in recent years for its diverse pharmacological characteristics. Increasing evidences reveal that ISO can inhibit cancer cell growth by induced apoptosis, however, the molecular mechanisms is not fully understood. In this study, we found for the first time that ISO apparently induced cell growth inhibition and apoptosis by targeting EGFR and its downstream signal pathways in prostate cancer (PCa) cells both in vitro and in vivo, whereas no obviously effect on normal prostate cells. From the results, we found that ISO competitively targeted EGFR with EGF and inhibited EGFR auto-phosphorylation, and then decreased the levels of p-Erk1/2, p-PI3 K, and p-AKT, and further induced down-regulation of p-FOXO1 and promoted FOXO1 nuclear translocation; and finally resulted in a significantly up-regulation of Bim/p21/27/Bax/cleaved Caspase-3/cleaved PARP-1 and a markedly down-regulation of Sp1/Bcl-2/XIAP/Cyclin D1. Moreover, our experimental data demonstrated that treatment of ISO decreased protein level of AR via both inhibiting the expression of AR gene and promoting the ubiquitination/degradation of AR proteins in proteasome. In vivo, we also found that ISO inhibited the growth of subcutaneous xenotransplanted tumor in nude mice by inducing PCa cell growth inhibition and apoptosis. Taken together, all findings here clearly implicated that EGFR-related signal pathways, including EGFR-PI3K-Akt and EGFR-Erk1/2 pathways, were involved in ISO-induced cell growth inhibition and apoptosis in PCa cells, providing a more solid theoretical basis for the application of ISO to treat patients with prostate cancer in clinic.

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“…ISO at a concentration of 100 µM decreased prostate cancer LNCaP and CWR22Rv1 cells viability to 25% and 45%, respectively. On the other hand, the weak effect was exerted on BPH-1 and WPHY-1 cells, where cell viability was~80% after ISO treatment at the same treatment conditions [64]. This study showed that ISO might bind to epidermal growth factor receptor (EGFR) and inhibit its autophosphorylation and downstream signallings, such as PI3K/Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) pathway.…”

“…Another study showed anticancer activity of ISO against prostate cancer LNCaP and CWR22Rv1 cell lines. It should be emphasized that ISO did not affect cell viability against benign hyperplasia epithelial cells (BPH-1) and healthy prostate cells (WPMY-1) [64]. It was shown using MTT assay that ISO inhibited the viability of LNCaP and CWR22Rv1 in a dose-dependent manner.…”

Chinese Medicines in the Treatment of Prostate Cancer: From Formulas to Extracts and Compounds

“…Isorhapontigenin (ISO) is widely distributed in Chinese herbs, fruits, and vegetables [ 54 , 55 , 56 ]. Isorhapontigenin (ISO, 20–100 μM) induced cell growth inhibition and apoptosis of LNCaP and 22Rv1 by targeting EGFR and its downstream signal pathways and showed no obvious effects on normal prostate cells [ 57 ]. Moreover, the treatment with ISO decreased the protein level of AR by promoting the ubiquitination and degradation of AR proteins in proteasome and inhibiting the expression of AR gene [ 57 ].…”

“…Isorhapontigenin (ISO, 20–100 μM) induced cell growth inhibition and apoptosis of LNCaP and 22Rv1 by targeting EGFR and its downstream signal pathways and showed no obvious effects on normal prostate cells [ 57 ]. Moreover, the treatment with ISO decreased the protein level of AR by promoting the ubiquitination and degradation of AR proteins in proteasome and inhibiting the expression of AR gene [ 57 ]. In vivo, 50 mg/kg of ISO inhibited the growth of subcutaneously xenotransplanted tumors in nude mice by inducing PCa cell growth inhibition and apoptosis [ 57 ].…”

“…Moreover, the treatment with ISO decreased the protein level of AR by promoting the ubiquitination and degradation of AR proteins in proteasome and inhibiting the expression of AR gene [ 57 ]. In vivo, 50 mg/kg of ISO inhibited the growth of subcutaneously xenotransplanted tumors in nude mice by inducing PCa cell growth inhibition and apoptosis [ 57 ]. EGFR-related signal pathways are involved in ISO-induced cell growth inhibition and apoptosis in PCa cells, suggesting the application potential of ISO in prostate cancer treatment.…”