PMID- 34205996 OWN - NLM STAT- MEDLINE DCOM- 20211027 LR - 20220716 IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 10 IP - 6 DP - 2021 Jun 1 TI - Dihydroartemisinin Inhibits mTORC1 Signaling by Activating the AMPK Pathway in Rhabdomyosarcoma Tumor Cells. LID - 10.3390/cells10061363 [doi] LID - 1363 AB - Dihydroartemisinin (DHA), an anti-malarial drug, has been shown to possess potent anticancer activity, partly by inhibiting the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling. However, how DHA inhibits mTORC1 is still unknown. Here, using rhabdomyosarcoma (RMS) as a model, we found that DHA reduced cell proliferation and viability in RMS cells, but not those in normal cells, which was associated with inhibition of mTORC1. Mechanistically, DHA did not bind to mTOR or FK506 binding protein 12 (FKBP12). In addition, DHA neither inhibited insulin-like growth factor-1 receptor (IGF-1R), phosphoinositide 3-kinase (PI3K), and extracellular signal-regulated kinase (1/2) (Erk1/2), nor activated phosphatase and tensin homolog (PTEN) in the cells. Rather, DHA activated AMP-activated protein kinase (AMPK). Pharmacological inhibition of AMPK, ectopic expression dominant negative or kinase-dead AMPK, or knockdown of AMPKa attenuated the inhibitory effect of DHA on mTORC1 in the cells. Additionally, DHA was able to induce dissociation of regulatory-associated protein of mTOR (raptor) from mTOR and inhibit mTORC1 activity. Moreover, treatment with artesunate, a prodrug of DHA, dose-dependently inhibited tumor growth and concurrently activated AMPK and suppressed mTORC1 in RMS xenografts. The results indicated that DHA inhibits mTORC1 by activating AMPK in tumor cells. Our finding supports that DHA or artesunate has a great potential to be repositioned for treatment of RMS. FAU - Luo, Jun AU - Luo J AD - Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. AD - College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China. FAU - Odaka, Yoshinobu AU - Odaka Y AUID- ORCID: 0000-0003-3966-5475 AD - Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. FAU - Huang, Zhu AU - Huang Z AD - Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. AD - Research Center of Aquatic Organism Conservation and Water Ecosystem Restoration in Anhui Province, Anqing Normal University, Anqing 246011, China. FAU - Cheng, Bing AU - Cheng B AD - Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. FAU - Liu, Wang AU - Liu W AD - Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. FAU - Li, Lin AU - Li L AD - Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. FAU - Shang, Chaowei AU - Shang C AD - Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. FAU - Zhang, Chao AU - Zhang C AD - Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. AD - Key Laboratory of National Health and Family Planning Commission on Parasitic Disease Control and Prevention, Jiangsu Institute of Parasitic Diseases, Wuxi 214064, China. AD - Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi 214064, China. FAU - Wu, Yang AU - Wu Y AD - Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China. FAU - Luo, Yan AU - Luo Y AD - Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China. FAU - Yang, Shengyong AU - Yang S AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China. FAU - Houghton, Peter J AU - Houghton PJ AD - Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229-3000, USA. FAU - Guo, Xiaofeng AU - Guo X AUID- ORCID: 0000-0003-2896-3629 AD - College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China. FAU - Huang, Shile AU - Huang S AUID- ORCID: 0000-0002-3239-1072 AD - Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. AD - Department of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. LA - eng GR - R01 CA115414/CA/NCI NIH HHS/United States GR - RSG-08-135-01-CNE/American Cancer Society/ GR - CA115414/NH/NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210601 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 0 (Artemisinins) RN - 0 (Neoplasm Proteins) RN - 6A9O50735X (artenimol) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinases/*metabolism MH - Artemisinins/*pharmacology MH - Cell Line, Tumor MH - Humans MH - Mechanistic Target of Rapamycin Complex 1/*metabolism MH - Neoplasm Proteins/*metabolism MH - Rhabdomyosarcoma/drug therapy/*metabolism MH - Signal Transduction/*drug effects PMC - PMC8226784 OTO - NOTNLM OT - AMPK OT - PTEN OT - dihydroartemisinin OT - mTOR OT - raptor OT - rhabdomyosarcoma COIS- The authors declare no competing financial interests. EDAT- 2021/07/03 06:00 MHDA- 2021/10/28 06:00 PMCR- 2021/06/01 CRDT- 2021/07/02 01:26 PHST- 2021/03/19 00:00 [received] PHST- 2021/05/26 00:00 [revised] PHST- 2021/05/29 00:00 [accepted] PHST- 2021/07/02 01:26 [entrez] PHST- 2021/07/03 06:00 [pubmed] PHST- 2021/10/28 06:00 [medline] PHST- 2021/06/01 00:00 [pmc-release] AID - cells10061363 [pii] AID - cells-10-01363 [pii] AID - 10.3390/cells10061363 [doi] PST - epublish SO - Cells. 2021 Jun 1;10(6):1363. doi: 10.3390/cells10061363.