Agrimol B inhibits colon carcinoma progression by blocking mitochondrial function through the PGC-1α/NRF1/TFAM signaling pathway
BackgroundThe 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 co...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.1055126/full |
| _version_ | 1811178157526482944 |
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| author | Dongyang Xiang Dongyang Xiang Wenjuan Yang Zihan Fang Jialei Mao Qiuying Yan Liu Li Liu Li Jiani Tan Jiani Tan Chengtao Yu Chengtao Yu Jun Qian Jun Qian Jun Qian Dongxin Tang Xiaoting Pan Haibo Cheng Haibo Cheng Haibo Cheng Dongdong Sun Dongdong Sun |
| author_facet | Dongyang Xiang Dongyang Xiang Wenjuan Yang Zihan Fang Jialei Mao Qiuying Yan Liu Li Liu Li Jiani Tan Jiani Tan Chengtao Yu Chengtao Yu Jun Qian Jun Qian Jun Qian Dongxin Tang Xiaoting Pan Haibo Cheng Haibo Cheng Haibo Cheng Dongdong Sun Dongdong Sun |
| author_sort | Dongyang Xiang |
| collection | DOAJ |
| description | BackgroundThe 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.MethodsThe 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.ResultsThe 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.ConclusionsOur 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. |
| first_indexed | 2024-04-11T06:14:48Z |
| format | Article |
| id | doaj.art-fe8ea4d285084acc931d8de36d912b29 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-11T06:14:48Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-fe8ea4d285084acc931d8de36d912b292022-12-22T04:41:06ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-12-011210.3389/fonc.2022.10551261055126Agrimol B inhibits colon carcinoma progression by blocking mitochondrial function through the PGC-1α/NRF1/TFAM signaling pathwayDongyang Xiang0Dongyang Xiang1Wenjuan Yang2Zihan Fang3Jialei Mao4Qiuying Yan5Liu Li6Liu Li7Jiani Tan8Jiani Tan9Chengtao Yu10Chengtao Yu11Jun Qian12Jun Qian13Jun Qian14Dongxin Tang15Xiaoting Pan16Haibo Cheng17Haibo Cheng18Haibo Cheng19Dongdong Sun20Dongdong Sun21College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, ChinaJiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, ChinaOncology Department, Kunshan Hospital Affiliated to Nanjing University of Chinese Medicine, Kunshan, ChinaJiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, ChinaOncology Department, Kunshan Hospital Affiliated to Nanjing University of Chinese Medicine, Kunshan, ChinaJiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, ChinaJiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, ChinaThe First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, ChinaJiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, ChinaThe First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, ChinaJiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, ChinaThe First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, ChinaJiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, ChinaThe First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, ChinaDepartment of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, ChinaCollege of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, ChinaOncology Department, Kunshan Hospital Affiliated to Nanjing University of Chinese Medicine, Kunshan, ChinaJiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, ChinaThe First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, ChinaDepartment of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, ChinaJiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaBackgroundThe 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.MethodsThe 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.ResultsThe 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.ConclusionsOur 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.https://www.frontiersin.org/articles/10.3389/fonc.2022.1055126/fullagrimol Bcolorectal cancerPGC-1αROSmitochondrial activity |
| spellingShingle | Dongyang Xiang Dongyang Xiang Wenjuan Yang Zihan Fang Jialei Mao Qiuying Yan Liu Li Liu Li Jiani Tan Jiani Tan Chengtao Yu Chengtao Yu Jun Qian Jun Qian Jun Qian Dongxin Tang Xiaoting Pan Haibo Cheng Haibo Cheng Haibo Cheng Dongdong Sun Dongdong Sun Agrimol B inhibits colon carcinoma progression by blocking mitochondrial function through the PGC-1α/NRF1/TFAM signaling pathway Frontiers in Oncology agrimol B colorectal cancer PGC-1α ROS mitochondrial activity |
| title | Agrimol B inhibits colon carcinoma progression by blocking mitochondrial function through the PGC-1α/NRF1/TFAM signaling pathway |
| title_full | Agrimol B inhibits colon carcinoma progression by blocking mitochondrial function through the PGC-1α/NRF1/TFAM signaling pathway |
| title_fullStr | Agrimol B inhibits colon carcinoma progression by blocking mitochondrial function through the PGC-1α/NRF1/TFAM signaling pathway |
| title_full_unstemmed | Agrimol B inhibits colon carcinoma progression by blocking mitochondrial function through the PGC-1α/NRF1/TFAM signaling pathway |
| title_short | Agrimol B inhibits colon carcinoma progression by blocking mitochondrial function through the PGC-1α/NRF1/TFAM signaling pathway |
| title_sort | agrimol b inhibits colon carcinoma progression by blocking mitochondrial function through the pgc 1α nrf1 tfam signaling pathway |
| topic | agrimol B colorectal cancer PGC-1α ROS mitochondrial activity |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.1055126/full |
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