Anticancer Effect of Involucrasin A on Colorectal Cancer Cells by Modulating the Akt/MDM2/p53 Pathway

Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide; however, there is still a lack of effective clinical anti-CRC agents. Naturally-occurring compounds have been considered a potentially valuable source of new antitumorigenic agents. Involucrasin A, a novel natural molecule, was isolated from Shuteria involucrata (Wall.) Wight & Arn by our team. In the present study, the anticancer activity of involucrasin A in HCT-116 CRC cells was evaluated. Firstly, the anti-proliferative effect of involucrasin A on HCT-116 cells was analyzed by sulforhodamine B and colony formation assays. The results revealed that involucrasin A exhibited a potent inhibitory effect on HCT-116 CRC cell proliferation in vitro. Subsequently, flow cytometry and western blotting indicated that involucrasin A induced apoptosis and upregulated the expression levels of apoptosis-related proteins, such as cleaved-caspase 6 and cleaved-caspase 9, in a dose-dependent manner. Mechanistically, involucrasin A significantly inhibited the phosphorylation of Akt and murine double minute 2 homologue (MDM2), which resulted in increased intracellular levels of p53. This was reversed by exogenous expression of the constitutively active form of Akt. Similarly, either knocking out p53 or knocking down Bax abrogated involucrasin A-induced proliferation inhibition and apoptosis. Together, the present study indicated that involucrasin A exerts antitumorigenic activities via modulating the Akt/MDM2/p53 pathway in HCT-116 CRC cells, and it is worthy of further exploration in preclinical and clinical trials.