Direct binding of arsenic trioxide to AMPK and generation of inhibitory effects on acute myeloid leukemia precursors

Elspeth M. Beauchamp, Ewa M. Kosciuczuk, Ruth Serrano, Dhaval Nanavati, Elden P. Swindell, Benoit Viollet, Thomas V. O'Halloran, Jessica K. Altman, Leonidas C. Platanias*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Arsenic trioxide (As2O3) exhibits potent antineoplastic effects and is used extensively in clinical oncology for the treatment of a subset of patients with acute myeloid leukemia (AML). Although As2O3 is known to regulate activation of several signaling cascades, the key events, accounting for its antileukemic properties, remain to be de fined. We provide evidence that arsenic can directly bind to cysteine 299 in AMPKα and inhibit its activity. This inhibition of AMPK by arsenic is required in part for its cytotoxic effects on primitive leukemic progenitors from patients with AML, while concomitant treatment with an AMPK activator antagonizes in vivo the arsenic-induced antileukemic effects in a xenograft AML mouse model. A consequence of AMPK inhibition is activation of the mTOR pathway as a negative regulatory feedback loop. However, when AMPK expression is lost, arsenic-dependent activation of the kinase RSK downstream of MAPK activity compensates the generation of regulatory feedback signals through phosphorylation of downstream mTOR targets. Thus, therapeutic regimens with As2O3 will need to include inhibitors of both the mTOR and RSK pathways in combination to prevent engagement of negative feedback loops and maximize antineoplastic responses.

Original languageEnglish (US)
Pages (from-to)202-212
Number of pages11
JournalMolecular cancer therapeutics
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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