Xanthohumol Inhibits The Proliferation Of Prostate Cancer Cells By Reducing The Activity Of Notch Signaling Pathway

Notch is a highly conserved signaling pathway, which is widely expressed from invertebrates to mammals. Notch signaling pathway plays an important role in the regulation of stem cell differentiation, cell proliferation, apoptosis and other cellular processes. Abnormal regulation of Notch signaling pathway plays a key role in a variety of human cancers. Notch signaling pathway has been an important target for the treatment of a variety of malignancies.Xanthohumol, as a prenylflavonoid, only exists in hops. Xanthohumol has a variety of biological activities, which can prevent diabetes and arterial sclerosis, it also has anti-oxidant activity and anti-cancer effect. Xanthohumol can inhibit the growth of various cancers including breast cancer, colon cancer, ovarian cancer, prostate cancer, etc. However, the specific molecular mechanism of xanthohumol is still unclear. As Notch signaling pathway plays an important role in cancer cells, and it shows a highly activated state in prostate cancer cells, we speculate that xanthohumol may inhibit survival and growth of prostate cancer cells through the regulation of Notch signaling pathway.This paper aims to explore the Notch signaling pathway as the target of xanthohumol and the anti-tumor activity mechanism of xanthohumol. First, Notch dependent luciferase reporter plasmids were transfected in prostate cancer cells and stably transfected cell lines were constructed. By this stably transfected cell lines, a variety of natural small molecules were screened. Luckily, xanthohumol, a kind of natural products, was screened as an inhibitor of Notch signaling pathway. Determined by MTT assay, xanthohumol showed a low toxicity to cells in12hours, and cell activity was higher than80%. While xanthohumol could inhibit cell proliferation in24hours. By flow cytometry and western blot analysis, xanthohumol could inhibit the cell cycle in Go/G1phase, meanwhile xanthohumol promoted apoptosis of prostate cells. By further cell transfection experiments, immunoblotting and RT-PCR experiments, we explored xanthohumol molecular targets in cells. Studies found that GSK-3β is closely related with the Notch signaling pathway. GSK-3β can inhibite Notch signaling pathway activity, so GSK-3β can be regarded as inhibitory protein of Notch signaling pathway. At last, we found that xanthohumol could inhibit Notch signaling pathway via the inhibition of GSK-3β Phosphorylation in prostate cancer cells.In summary, xanthohumol could inhibit the growth of prostate cancer cells through the inhibition of Notch signaling pathway activity in prostate cancer cells. This study explains the molecular mechanism of xanthohumol with anti-tumor activity, and provides us a basis theoretical that xanthohumol may serve as a potent inhibitor of Notch signaling pathway for the treatment of prostate cancer.