BMP9 mediates the anticancer activity of evodiamine through HIF‑1α/p53 in human colon cancer cells

Abstract

Colon cancer is one of the most common malignancies. Although there has been great development in treatment regimens over the last few decades, its prognosis remains poor. There is still a clinical need to find new drugs for colon cancer. Evodiamine (Evo) is a quinolone alkaloid extracted from the traditional herbal medicine plant Evodia rutaecarpa. In the present study, CCK-8, flow cytometry, reverse transcription quantitative polymerase chain reaction, western blot analysis and a xenograft tumor model were used to evaluate the anti-cancer activity of Evo in human colon cancer cells and determine the possible mechanism underlying this process. It was revealed that Evo exhibited prominent anti-proliferation and apoptosis-inducing effects in HCT116 cells. Bone morphogenetic protein 9 (BMP9) was notably upregulated by Evo in HCT116 cells. Exogenous BMP9 potentiated the anti-cancer activity of Evo, and BMP9 silencing reduced this effect. In addition, HIF-1α was also upregulated by Evo. The anticancer activity of Evo was enhanced by HIF-1α, but was reduced by HIF-1α silencing. BMP9 potentiated the effect of Evo on the upregulation of HIF-1α, and enhanced the antitumor effect of Evo in colon cancer, which was clearly reduced by HIF-1α silencing. In HCT116 cells, Evo increased the phosphorylation of p53, which was enhanced by BMP9 but reduced by BMP9 silencing. Furthermore, the effect of Evo on p53 was potentiated by HIF-1α and reduced by HIF-1α silencing. The present findings therefore strongly indicated that the anticancer activity of Evo may be partly mediated by BMP9 upregulation, which can activate p53 through upregulation of HIF-1α, at least in human colon cancer.

Identification of liver‐derived bone morphogenetic protein (BMP)‐9 as a potential new candidate for treatment of colorectal cancer

“…This is in line with the aggressive course of disease of P090, as well as published results from a different cohort 23 . Interestingly, a correlation between BMP‐9 and p53 has been described earlier by Li et al 43 : in a human CRC cell line (HCT116), BMP‐9 promotes p53 activity and thereby reduces tumour growth in a xenotransplantation mouse model.…”

Colorectal Cancer and Bone Tissue: Fantastic Relations and Where to Find Them

“…By treating HCT116 cells with Evo and using these cells to induce cancer in a mouse model following injection into the hip, the mechanism of the anticancer effect in CRC of Evo and BMP9 was investigated. In those experiments where BMP9 was overexpressed or silenced in HCT116, the antitumor action of Evo, its upregulation of HIF-α and its activation of the oncosuppressor p53 increased with BMP9 and was decreased by silencing BMP9 [52].…”

“…The involvement of BMP9 in colonic tumorigenesis has also been highlighted by an interesting and recent study on the potential beneficial anti-neoplastic effects of a natural component against CRC [52]. This study demonstrated that evodiamine (Evo), a quinolone alkaloid extracted from traditional herbal medicine Evodia rutaecarpa, had an antitumor activity, and the authors tried to elucidate its molecular mechanisms.…”

The Landscape of Interactions between Hypoxia‐Inducible Factors and Reactive Oxygen Species in the Gastrointestinal Tract

“…In line with this, the 4-(2-phenylpyridin-4-yl)pyrazoles exerted antiproliferation and apoptosis-inducing effect by inhibiting the activation of HIF-1 α in HCT116 cells [ 43 ]. However, the evodiamine treatment suppressed proliferation and induced apoptosis by upregulating bone morphogenetic protein 9 (BMP9), which could activate p53 via the upregulation of the HIF-1 α in HCT116 cells [ 44 ].…”