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

Chaowei Shang1,2, Hongyu Zhou1, Wang Liu1

  • 1Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130-3932, USA.

Oncogene
|June 17, 2020
PubMed

Insights

Iron chelators inhibit mammalian target of rapamycin complex 1 (mTORC1) signaling, a key pathway in cell growth and cancer. This inhibition is iron-dependent and involves multiple cellular pathways, highlighting iron

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Mammalian target of rapamycin (mTOR) signaling, via mTORC1 and mTORC2 complexes, regulates cell growth and metabolism.
  • Aberrant mTOR signaling is implicated in various cancers, making it a therapeutic target.
  • Iron chelators show anticancer potential, but their precise mechanisms, especially concerning mTOR, remain unclear.

Purpose of the Study:

  • To elucidate the effects of iron chelation on mTOR signaling pathways.
  • To investigate the mechanistic basis of iron chelation-induced mTORC1 inhibition.
  • To determine the role of iron in mTORC1 activation.

Main Methods:

  • Treatment of cells with iron chelators and ferrous sulfate.
  • Analysis of mTORC1 signaling components.
  • Investigation of reactive oxygen species (ROS), copper chelation, PP2A activation, AMPK, HIF-1/REDD1, and Bnip3 pathways.

Main Results:

  • Iron chelators consistently inhibited mTORC1 signaling in a manner reversible by ferrous sulfate.
  • Iron chelation-induced mTORC1 inhibition was independent of ROS, copper chelation, or PP2A activation.
  • The AMPK pathway was identified as a major contributor, with partial contributions from HIF-1/REDD1 and Bnip3 pathways.

Conclusions:

  • Iron chelation inhibits mTORC1 signaling through multiple pathways, including AMPK, HIF-1/REDD1, and Bnip3.
  • Iron is essential for the activation of mTORC1.
  • These findings provide mechanistic insights into the anticancer effects of iron chelators.

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