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

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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 200 μg/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 (100 μg/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.

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Data Availability

The data sets used and analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ANOVA :

One-way analysis of variance

ASPA :

Asperulosidic acid

CCK8 :

Cell Counting Kits-8

CDK2 :

Cyclin-dependent kinase 2

CDDP :

Cisplatin;

Dox :

Doxorubicin

EMT :

Epithelial-mesenchymal transition

HCC :

Hepatocellular carcinoma;

IHC :

Immunohistochemistry

ING4 :

Inhibitor of growth 4

MEKK1 :

Mitogen-activated protein kinase kinase kinase 1

NC :

Negative control

NS :

No significance

NF-κB :

Nuclear factor-kappaB

OD :

Optical density

PBS :

Phosphate-buffered solution

RT-PCR :

Reverse transcription-polymerase chain reaction

SD :

Standard deviation

WB :

Western blot

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Funding

The work was funded by grants from the Key Discipline of Hepatobiliary and Pancreatic Surgery of Jiaxing City [2023-ZC-005], Translational therapy center for hepatobiliary pancreatic cancer [2021-YJZX-04].

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  1. Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, No.1882 South Zhong Huan Road, Jiaxing City, Zhejiang Province, 314001, China

    Liang Li & Huiwen Qiu

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  1. Liang Li
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Conceived and designed the experiments: Huiwen Qiu; performed the experiments: Liang Li; statistical analysis: Liang Li; wrote the paper: Liang Li, Huiwen Qiu. All authors read and approved the final manuscript.

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Correspondence to Huiwen Qiu.

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Li, L., Qiu, H. Asperulosidic Acid Restrains Hepatocellular Carcinoma Development and Enhances Chemosensitivity Through Inactivating the MEKK1/NF-κB Pathway. Appl Biochem Biotechnol 196, 1–17 (2024). https://doi.org/10.1007/s12010-023-04500-2

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