Agrimol B inhibits colon carcinoma progression by blocking mitochondrial function through the PGC-1α/NRF1/TFAM signaling pathway

Dongyang Xiang; Wenjuan Yang; Zihan Fang; Jialei Mao; Qiuying Yan; Liu Li; Jiani Tan; Chengtao Yu; Jun Qian; Dongxin Tang; Xiaoting Pan; Haibo Cheng; Dongdong Sun

doi:10.3389/fonc.2022.1055126

Agrimol B inhibits colon carcinoma progression by blocking mitochondrial function through the PGC-1α/NRF1/TFAM signaling pathway

Front Oncol. 2022 Dec 14:12:1055126. doi: 10.3389/fonc.2022.1055126. eCollection 2022.

Authors

Dongyang Xiang^{1

2}, Wenjuan Yang³, Zihan Fang², Jialei Mao³, Qiuying Yan², Liu Li^{2

4}, Jiani Tan^{2

4}, Chengtao Yu^{2

4}, Jun Qian^{2

4

5}, Dongxin Tang¹, Xiaoting Pan³, Haibo Cheng^{2

4

5}, Dongdong Sun^{2

6}

Affiliations

¹ College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, China.
² Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China.
³ Oncology Department, Kunshan Hospital Affiliated to Nanjing University of Chinese Medicine, Kunshan, China.
⁴ The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China.
⁵ Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
⁶ School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.

Abstract

Background: The activation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) stimulates the transcription of the downstream target proteins, mitochondrial transcription factor A (TFAM) and nuclear respiratory factor 1 (NRF1), which induces mitochondrial biogenesis and promotes colorectal tumorigenesis. Agrimol B (Agr) is a constituent of Agrimonia pilosa Ledeb. that exerts anticancer effects. Herein, we aimed to investigate the antitumor activity of Agr and its mechanism of action.

Methods: The interaction between Agr and PGC-1α was predicted by molecular docking. After the treatment with different concentrations of Agr (0, 144, 288, and 576 nM), the cell viability, migration rate, proliferation rate, and apoptosis rate of human colon cancer HCT116 cells were determined. Mitochondrial activity, cellular reactive oxygen species (ROS), and mitochondrial membrane potential were assessed to measure the regulatory effect of Agr on mitochondrial function. Western blotting (WB) assay was used to examine the expression of PGC-1α, NRF1, and TFAM, as well as of the pro-apoptotic proteins, Bax and Caspase-3, and the antiapoptotic protein (Bcl-2). Finally, subcutaneous tumor xenograft model mice were used to evaluate the effect of Agr on colorectal cancer (CRC) in vivo.

Results: The molecular docking results revealed a high likelihood of Agr interacting with PGC-1α. Agr inhibited the proliferation and migration of HCT116 cells, promoted ROS production and mitochondrial oxidative stress, inhibited mitochondrial activity, and decreased mitochondrial membrane potential. Agr induced cell apoptosis and, in combination with PGC-1α, impaired mitochondrial biogenesis and suppressed the expression of NRF1 and TFAM. Agr also suppressed the expression of Bcl-2 and Cleaved-Caspase-3 and increased the expression of Bax and Caspase-3. In addition, the in vivo antitumor effect and mechanism of Agr were confirmed by using a subcutaneous tumor xenograft mouse model.

Conclusions: Our findings demonstrated that Agr regulates the expression of PGC-1α, thereby inducing mitochondrial dysfunction and promoting tumor cell apoptosis. This work highlights the potential of Agr as a promising therapeutic candidate in CRC.

Keywords: PGC-1α; ROS; agrimol B; colorectal cancer; mitochondrial activity.