PMID- 28675698 OWN - NLM STAT- MEDLINE DCOM- 20180423 LR - 20220317 IS - 2045-7634 (Electronic) IS - 2045-7634 (Linking) VI - 6 IP - 8 DP - 2017 Aug TI - The mTOR inhibition in concurrence with ERK1/2 activation is involved in excessive autophagy induced by glycyrrhizin in hepatocellular carcinoma. PG - 1941-1951 LID - 10.1002/cam4.1127 [doi] AB - Autophagy is a life phenomenon in which autophagosomes remove damaged or aging organelles and long-lived circulating proteins to maintain the cell's stability. However, disorders of excessive autophagy are a response of cancer cells to a variety of anticancer treatments which lead to cancer cell death. The Akt/mammalian target of rapamycin (mTOR) and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathways are both involved in nutrient-induced autophagic phenomenon and exhibit vital relevance to oncogenesis in various cancer cell types, including hepatocellular carcinoma (HCC). However, the influence of autophagy for cancer cell death remains controversial and few scientists have investigated the variation of these two signaling pathways in cancer cell autophagic phenomenon induced by anticancer treatment simultaneously. Here, we explored the anticancer efficacy and mechanisms of glycyrrhizin (GL), a bioactive compound of licorice with little toxicity in normal cells. It is interesting that inhibition of Akt/mTOR signaling in concurrence with enhanced ERK1/2 activity exists in GL-induced autophagy and cytotoxicity in HepG2 and MHCC97-H hepatocellular carcinoma cells. These results imply that the GL-related anticancer ability might correlate with the induction of autophagy. The influence of induced autophagic phenomenon on cell viability might depend on the severity of autophagy and be pathway specific. In the subsequent subcutaneous xenograft experiment in vivo with MHCC97-H cells, GL obviously exhibited its inhibitory efficacy in tumor growth via inducing excess autophagy in MHCC97-H cells (P < 0.05). Our data prompt that GL possesses a property of excess autophagic phenomenon induction in HCC and exerts high anticancer efficacy in vitro and in vivo. This warrants further investigation toward possible clinical applications in patients with HCC. CI - (c) 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. FAU - Zhang, Xuan AU - Zhang X AUID- ORCID: 0000-0003-2937-9141 AD - Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Yang, Hua AU - Yang H AD - Department of Geriatrics, Xi'an No. 1 Hospital, Xi'an, Shaanxi, China. FAU - Yue, Shuqiang AU - Yue S AD - Department of Oncological Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - He, Guangbin AU - He G AD - Department of Ultrasound Diagnosis, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Qu, Shibin AU - Qu S AD - Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Zhang, Zhuochao AU - Zhang Z AD - Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Ma, Ben AU - Ma B AD - Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Ding, Rui AU - Ding R AD - Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Peng, Wei AU - Peng W AD - Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Zhang, Hongtao AU - Zhang H AD - Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Yang, Zhaoxu AU - Yang Z AD - Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Dou, Kefeng AU - Dou K AD - Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Tao, Kaishan AU - Tao K AD - Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Li, Xiao AU - Li X AD - Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. LA - eng PT - Journal Article DEP - 20170703 PL - United States TA - Cancer Med JT - Cancer medicine JID - 101595310 RN - 6FO62043WK (Glycyrrhizic Acid) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) SB - IM MH - Animals MH - Autophagy/*drug effects MH - Carcinoma, Hepatocellular/*metabolism/pathology MH - Cell Line, Tumor MH - Cell Movement/drug effects MH - Cell Proliferation/drug effects MH - Cell Survival/drug effects MH - Disease Models, Animal MH - Female MH - Glycyrrhizic Acid/chemistry/*pharmacology MH - Humans MH - Liver Neoplasms/*metabolism/pathology MH - Mice MH - Mitogen-Activated Protein Kinase 1/*metabolism MH - Mitogen-Activated Protein Kinase 3/*metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors MH - Xenograft Model Antitumor Assays PMC - PMC5548872 OTO - NOTNLM OT - Autophagy OT - ERK1/2 OT - glycyrrhizin OT - hepatocellular carcinoma OT - mTOR EDAT- 2017/07/05 06:00 MHDA- 2018/04/24 06:00 PMCR- 2017/07/03 CRDT- 2017/07/05 06:00 PHST- 2016/07/09 00:00 [received] PHST- 2017/04/12 00:00 [revised] PHST- 2017/05/18 00:00 [accepted] PHST- 2017/07/05 06:00 [pubmed] PHST- 2018/04/24 06:00 [medline] PHST- 2017/07/05 06:00 [entrez] PHST- 2017/07/03 00:00 [pmc-release] AID - CAM41127 [pii] AID - 10.1002/cam4.1127 [doi] PST - ppublish SO - Cancer Med. 2017 Aug;6(8):1941-1951. doi: 10.1002/cam4.1127. Epub 2017 Jul 3.