Antrodia camphorata Mycelia Exert Anti-liver Cancer Effects and Inhibit STAT3 Signaling in vitro and in vivo
Hepatocellular carcinoma (HCC), the major form of primary liver cancer, is a common cause of cancer-related death worldwide. Signal transducer and activator of transcription 3 (STAT3) signaling is constantly activated in HCC and has been proposed as a chemotherapeutic target for HCC. Antrodia campho...
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Frontiers Media S.A.
2018-12-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2018.01449/full |
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language |
English |
format |
Article |
sources |
DOAJ |
author |
Pei-Li Zhu Pei-Li Zhu Pei-Li Zhu Xiu-Qiong Fu Xiu-Qiong Fu Xiu-Qiong Fu Jun-Kui Li Jun-Kui Li Jun-Kui Li Anfernee Kai-Wing Tse Hui Guo Hui Guo Hui Guo Cheng-Le Yin Cheng-Le Yin Cheng-Le Yin Ji-Yao Chou Ji-Yao Chou Ji-Yao Chou Ya-Ping Wang Ya-Ping Wang Ya-Ping Wang Yu-Xi Liu Yu-Xi Liu Yu-Xi Liu Ying-Jie Chen Ying-Jie Chen Ying-Jie Chen Muhammad Jahangir Hossen Yi Zhang Si-Yuan Pan Zong-Jie Zhao Zhi-Ling Yu Zhi-Ling Yu Zhi-Ling Yu |
spellingShingle |
Pei-Li Zhu Pei-Li Zhu Pei-Li Zhu Xiu-Qiong Fu Xiu-Qiong Fu Xiu-Qiong Fu Jun-Kui Li Jun-Kui Li Jun-Kui Li Anfernee Kai-Wing Tse Hui Guo Hui Guo Hui Guo Cheng-Le Yin Cheng-Le Yin Cheng-Le Yin Ji-Yao Chou Ji-Yao Chou Ji-Yao Chou Ya-Ping Wang Ya-Ping Wang Ya-Ping Wang Yu-Xi Liu Yu-Xi Liu Yu-Xi Liu Ying-Jie Chen Ying-Jie Chen Ying-Jie Chen Muhammad Jahangir Hossen Yi Zhang Si-Yuan Pan Zong-Jie Zhao Zhi-Ling Yu Zhi-Ling Yu Zhi-Ling Yu Antrodia camphorata Mycelia Exert Anti-liver Cancer Effects and Inhibit STAT3 Signaling in vitro and in vivo Frontiers in Pharmacology Antrodia camphorata mycelia liver cancer cell viability apoptosis metastasis STAT3 signaling |
author_facet |
Pei-Li Zhu Pei-Li Zhu Pei-Li Zhu Xiu-Qiong Fu Xiu-Qiong Fu Xiu-Qiong Fu Jun-Kui Li Jun-Kui Li Jun-Kui Li Anfernee Kai-Wing Tse Hui Guo Hui Guo Hui Guo Cheng-Le Yin Cheng-Le Yin Cheng-Le Yin Ji-Yao Chou Ji-Yao Chou Ji-Yao Chou Ya-Ping Wang Ya-Ping Wang Ya-Ping Wang Yu-Xi Liu Yu-Xi Liu Yu-Xi Liu Ying-Jie Chen Ying-Jie Chen Ying-Jie Chen Muhammad Jahangir Hossen Yi Zhang Si-Yuan Pan Zong-Jie Zhao Zhi-Ling Yu Zhi-Ling Yu Zhi-Ling Yu |
author_sort |
Pei-Li Zhu |
title |
Antrodia camphorata Mycelia Exert Anti-liver Cancer Effects and Inhibit STAT3 Signaling in vitro and in vivo |
title_short |
Antrodia camphorata Mycelia Exert Anti-liver Cancer Effects and Inhibit STAT3 Signaling in vitro and in vivo |
title_full |
Antrodia camphorata Mycelia Exert Anti-liver Cancer Effects and Inhibit STAT3 Signaling in vitro and in vivo |
title_fullStr |
Antrodia camphorata Mycelia Exert Anti-liver Cancer Effects and Inhibit STAT3 Signaling in vitro and in vivo |
title_full_unstemmed |
Antrodia camphorata Mycelia Exert Anti-liver Cancer Effects and Inhibit STAT3 Signaling in vitro and in vivo |
title_sort |
antrodia camphorata mycelia exert anti-liver cancer effects and inhibit stat3 signaling in vitro and in vivo |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2018-12-01 |
description |
Hepatocellular carcinoma (HCC), the major form of primary liver cancer, is a common cause of cancer-related death worldwide. Signal transducer and activator of transcription 3 (STAT3) signaling is constantly activated in HCC and has been proposed as a chemotherapeutic target for HCC. Antrodia camphorata (AC), a medicinal mushroom unique to Taiwan, is traditionally used for treating HCC. Whereas natural AC is scarce, cultured AC mycelia are becoming alternatives. In this study, we investigated the anti-HCC effects of the ethyl acetate fraction of an ethanolic extract of AC mycelia (EEAC), particularly exploring the involvement of STAT3 signaling in these effects. We found that EEAC reduced cell viability, induced apoptosis, and retarded migration and invasion in cultured HepG2 and SMMC-7721 cells. Immunoblotting results showed that EEAC downregulated protein levels of phosphorylated and total STAT3 and JAK2 (an upstream kinase of STAT3) in HCC cells. Real-time PCR analyses showed that STAT3, but not JAK2, mRNA levels were decreased by EEAC. EEAC also lowered the protein level of nuclear STAT3, decreased the transcriptional activity of STAT3, and downregulated protein levels of STAT3-targeted molecules, including anti-apoptotic proteins Bcl-xL and Bcl-2, and invasion-related proteins MMP-2 and MMP-9. Over-activation of STAT3 in HCC cells diminished the cytotoxic effects of EEAC. In SMMC-7721 cell-bearing mice, EEAC (100 mg/kg, i.g. for 18 days) significantly inhibited tumor growth. Consistent with our in vitro data, EEAC induced apoptosis and suppressed JAK2/STAT3 activation/phosphorylation in the tumors. Taken together, EEAC exerts anti-HCC effects both in vitro and in vivo; and inhibition of STAT3 signaling is, at least in part, responsible for these effects. We did not observe significant toxicity of EEAC in normal human liver-derived cells, nude mice and rats. Our results provide a pharmacological basis for developing EEAC as a safe and effective agent for HCC management. |
topic |
Antrodia camphorata mycelia liver cancer cell viability apoptosis metastasis STAT3 signaling |
url |
https://www.frontiersin.org/article/10.3389/fphar.2018.01449/full |
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doaj-c3a92b9ac3624e07975628bc73dcc73f2020-11-24T23:02:01ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-12-01910.3389/fphar.2018.01449382063Antrodia camphorata Mycelia Exert Anti-liver Cancer Effects and Inhibit STAT3 Signaling in vitro and in vivoPei-Li Zhu0Pei-Li Zhu1Pei-Li Zhu2Xiu-Qiong Fu3Xiu-Qiong Fu4Xiu-Qiong Fu5Jun-Kui Li6Jun-Kui Li7Jun-Kui Li8Anfernee Kai-Wing Tse9Hui Guo10Hui Guo11Hui Guo12Cheng-Le Yin13Cheng-Le Yin14Cheng-Le Yin15Ji-Yao Chou16Ji-Yao Chou17Ji-Yao Chou18Ya-Ping Wang19Ya-Ping Wang20Ya-Ping Wang21Yu-Xi Liu22Yu-Xi Liu23Yu-Xi Liu24Ying-Jie Chen25Ying-Jie Chen26Ying-Jie Chen27Muhammad Jahangir Hossen28Yi Zhang29Si-Yuan Pan30Zong-Jie Zhao31Zhi-Ling Yu32Zhi-Ling Yu33Zhi-Ling Yu34Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongResearch and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, ChinaConsun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongResearch and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, ChinaConsun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongResearch and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, ChinaCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongConsun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongResearch and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, ChinaConsun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongResearch and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, ChinaConsun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongResearch and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, ChinaConsun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongResearch and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, ChinaConsun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongResearch and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, ChinaConsun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongResearch and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, ChinaConsun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongResearch and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, ChinaShenzhen Union Assets Biological Technology Co., Ltd., Shenzhen, ChinaConsun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongResearch and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, ChinaHepatocellular carcinoma (HCC), the major form of primary liver cancer, is a common cause of cancer-related death worldwide. Signal transducer and activator of transcription 3 (STAT3) signaling is constantly activated in HCC and has been proposed as a chemotherapeutic target for HCC. Antrodia camphorata (AC), a medicinal mushroom unique to Taiwan, is traditionally used for treating HCC. Whereas natural AC is scarce, cultured AC mycelia are becoming alternatives. In this study, we investigated the anti-HCC effects of the ethyl acetate fraction of an ethanolic extract of AC mycelia (EEAC), particularly exploring the involvement of STAT3 signaling in these effects. We found that EEAC reduced cell viability, induced apoptosis, and retarded migration and invasion in cultured HepG2 and SMMC-7721 cells. Immunoblotting results showed that EEAC downregulated protein levels of phosphorylated and total STAT3 and JAK2 (an upstream kinase of STAT3) in HCC cells. Real-time PCR analyses showed that STAT3, but not JAK2, mRNA levels were decreased by EEAC. EEAC also lowered the protein level of nuclear STAT3, decreased the transcriptional activity of STAT3, and downregulated protein levels of STAT3-targeted molecules, including anti-apoptotic proteins Bcl-xL and Bcl-2, and invasion-related proteins MMP-2 and MMP-9. Over-activation of STAT3 in HCC cells diminished the cytotoxic effects of EEAC. In SMMC-7721 cell-bearing mice, EEAC (100 mg/kg, i.g. for 18 days) significantly inhibited tumor growth. Consistent with our in vitro data, EEAC induced apoptosis and suppressed JAK2/STAT3 activation/phosphorylation in the tumors. Taken together, EEAC exerts anti-HCC effects both in vitro and in vivo; and inhibition of STAT3 signaling is, at least in part, responsible for these effects. We did not observe significant toxicity of EEAC in normal human liver-derived cells, nude mice and rats. Our results provide a pharmacological basis for developing EEAC as a safe and effective agent for HCC management.https://www.frontiersin.org/article/10.3389/fphar.2018.01449/fullAntrodia camphorata mycelialiver cancercell viabilityapoptosismetastasisSTAT3 signaling |