Dihydroartemisinin Inhibits mTORC1 Signaling by Activating the AMPK Pathway in Rhabdomyosarcoma Tumor Cells.

Abstract

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 ½ (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.

• Authors: Jun Luo, Yoshinobu Odaka, Zhu Huang, Bing Cheng, Wang Liu, Lin Li, Chaowei Shang, Chao Zhang, Yang Wu, Yan Luo, Shengyong Yang, Peter J Houghton, Xiaofeng Guo, Shile Huang
• Journal: Cells (Cells) Vol. 10 Issue 6 (06 01 2021) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 34205996 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Artemisinins
• Neoplasm Proteins
• artenimol
• Mechanistic Target of Rapamycin Complex 1
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Artemisinins (pharmacology)
• Cell Line, Tumor
• Humans
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Neoplasm Proteins (metabolism)
• Rhabdomyosarcoma (drug therapy, metabolism)
• Signal Transduction (drug effects)