Asperulosidic Acid Restrains Hepatocellular Carcinoma Development and Enhances Chemosensitivity Through Inactivating the MEKK1/NF-κB Pathway.

Abstract

Asperulosidic acid (ASPA) is a plant-extracted iridoid terpenoid with tumor-suppressive and anti-inflammatory properties. At present, the antitumor function of ASPA and its related mechanisms in hepatocellular carcinoma (HCC) cells were explored. Human normal hepatocytes HL-7702 and HCC cells (Huh7 and HCCLM3) were treated with varying concentrations (0 to 200μg/mL) of ASPA. Cell viability, proliferation, apoptosis, migration, and invasion were checked. The expression of proteins was detected by Western blot. Furthermore, the effect of ASPA (100μg/mL) on the sensitivity of HCC cells to chemotherapeutic agents, including doxorubicin and cisplatin, was evaluated. A subcutaneous xenografted tumor model was set up in nude mice, and the antitumor effects of ASPA were evaluated. ASPA hindered HCC cells' proliferation, migration, and invasion, and amplified their apoptosis and sensitivity to chemotherapeutic agents. Additionally, ASPA inactivated the MEKK1/NF-κB pathway. Overexpression of MEKK1 increased HCC proliferation, migration, and invasion and facilitated chemoresistance. ASPA treatment alleviated the carcinogenic effect mediated by MEKK1 overexpression. MEKK1 knockdown slowed down HCC progression. However, ASPA could not exert additional antitumor effects in MEKK1 knockdown cells. In vivo results displayed that ASPA substantially curbed tumor growth and inactivated the MEKK1/NF-κB pathway in mice. All over, ASPA exerts antitumor effects in HCC by suppressing the MEKK1/NF-κB pathway.