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Iron chelation inhibits mTORC1 signaling involving activation of AMPK and REDD1/Bnip3 pathways.

Authors
  • Shang, Chaowei1, 2
  • Zhou, Hongyu1
  • Liu, Wang1
  • Shen, Tao1, 2
  • Luo, Yan1
  • Huang, Shile3, 4
  • 1 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130-3932, USA.
  • 2 Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, 71130-3932, USA.
  • 3 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130-3932, USA. [email protected]
  • 4 Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, 71130-3932, USA. [email protected]
Type
Published Article
Journal
Oncogene
Publisher
Nature Publishing Group UK
Publication Date
Jul 01, 2020
Volume
39
Issue
29
Pages
5201–5213
Identifiers
DOI: 10.1038/s41388-020-1366-5
PMID: 32541839
Source
Medline
Language
English
License
Unknown

Abstract

The mammalian target of rapamycin (mTOR) functions as two complexes (mTORC1 and mTORC2), regulating cell growth and metabolism. Aberrant mTOR signaling occurs frequently in cancers, so mTOR has become an attractive target for cancer therapy. Iron chelators have emerged as promising anticancer agents. However, the mechanisms underlying the anticancer action of iron chelation are not fully understood. Particularly, reports on the effects of iron chelation on mTOR complexes are inconsistent or controversial. Here, we found that iron chelators consistently inhibited mTORC1 signaling, which was blocked by pretreatment with ferrous sulfate. Mechanistically, iron chelation-induced mTORC1 inhibition was not related to ROS induction, copper chelation, or PP2A activation. Instead, activation of AMPK pathway mainly and activation of both HIF-1/REDD1 and Bnip3 pathways partially contribute to iron chelation-induced mTORC1 inhibition. Our findings indicate that iron chelation inhibits mTORC1 via multiple pathways and iron is essential for mTORC1 activation.

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