Hesperidin delays cell cycle progression into the G0/G1 phase via suspension of MAPK signaling pathway in intrahepatic cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (iCCA) derived from epithelial cells of bile ducts is highly aggressive tumor. Hesperidin extracted from citrus fruits is a promising antitumor compound. The purpose of this study is to explore molecular mechanism by which hesperidin affects cholangiocarcinoma progression. Cellular functional experiments were performed and subcutaneous transplant xenograft model was established. Our findings indicated that hesperidin suppressed iCCA cell proliferation in time‐ and concentration‐dependent manners. Hesperidin treatment induced cell cycle arrest at G0/G1 phase, whereas it has no effect on cell apoptosis. Further, data revealed that hesperidin attenuated MEK5 and ERK5 phosphorylation and inhibited ERK5 nuclear localization by reducing MEKK2 activity in MAPK signaling pathway. It could cause alterations in expression of the downstream genes, including CDK4, CDK6 (cell cycle protein kinases), Cyclin D1 (a G1/S checkpoint), P21, and P27 (two G1‐checkpoint CDK inhibitors), thereby arresting cell cycle distribution of iCCA cells in the G0/G1 phase. BIX02189 treatment, a specific inhibitor of MEK5, in combination with hesperidin displayed synergistic inhibitory effects on cell cycle arrest and gene expressions. Furthermore, hesperidin administration alone or in combination with MEK5 inhibitor BIX02189 restrained iCCA tumor growth in vivo. Taken together, these results confirmed that hesperidin regulated the expression of cell cycle‐related genes by inhibiting the activation of MEKK2/MEK5/ERK5 signaling pathway, inducing iCCA cell cycle arrest at the G0/G1 phase. Our study provides a theoretical foundation and experimental basis for further development of hesperidin as a therapeutic agent for iCCA treatment.

Hesperidin Suppresses the Proliferation of Prostate Cancer Cells by Inducing Oxidative Stress and Disrupting Ca2+ Homeostasis

“…Similar to our findings, a previous study reported that hesperidin inhibits the PI3K pathway in chemically induced liver cancer tissues in rats [ 62 ]. Hesperidin also regulates the expression of genes involved in cell cycle progression to arrest the cell cycle by inhibiting the MAPK pathway in intrahepatic cholangiocarcinoma [ 63 ]. To the best of our knowledge, this study is the first to analyze the effects of hesperidin on the MAPK and PI3K signaling pathways in prostate cancer cells.…”

Hesperidin inhibits tobacco smoke‑induced pulmonary cell proliferation and EMT in mouse lung tissues via the p38 signaling pathway

“…Dietary phytochemicals, such as hesperidin, are considered to contribute to cancer prevention (37,38). The safety of hesperidin and its anticancer activity have been previously demonstrated (41,65,66). The intervention of hesperidin in TS-induced abnormal pulmonary EMT and cell proliferation is through the p38 pathway, where phosphorylated p38 and phosphorylated c-Fos are attenuated by hesperidin.…”