Evaluating the iron chelator function of sirtinol in non-small cell lung cancer

Michael S. Petronek; Khaliunaa Bayanbold; Koffi Amegble; Ann M. Tomanek-Chalkley; Bryan G. Allen; Douglas R. Spitz; Charvann K. Bailey

doi:10.3389/fonc.2023.1185715

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Evaluating the iron chelator function of sirtinol in non-small cell lung cancer

Journal article

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Peer reviewed

Evaluating the iron chelator function of sirtinol in non-small cell lung cancer

Michael S. Petronek, Khaliunaa Bayanbold, Koffi Amegble, Ann M. Tomanek-Chalkley, Bryan G. Allen, Douglas R. Spitz and Charvann K. Bailey

Frontiers in oncology, Vol.13, 1185715

06/01/2023

DOI: 10.3389/fonc.2023.1185715

PMCID: PMC10313412

PMID: 37397370

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Abstract

A distinctive feature of cancer is the upregulation of sirtuin proteins. Sirtuins are class III NAD+-dependent deacetylases involved in cellular processes such as proliferation and protection against oxidative stress. SIRTs 1 and 2 are also overexpressed in several types of cancers including non-small cell lung cancer (NSCLC). Sirtinol, a sirtuin (SIRT) 1 and 2 specific inhibitor, is a recent anti-cancer agent that is cytotoxic against several types of cancers including NSCLC. Thus, sirtuins 1 and 2 represent valuable targets for cancer therapy. Recent studies show that sirtinol functions as a tridentate iron chelator by binding Fe3+ with 3:1 stoichiometry. However, the biological consequences of this function remain unexplored. Consistent with preliminary literature, we show that sirtinol can deplete intracellular labile iron pools in both A549 and H1299 non-small cell lung cancer cells acutely. Interestingly, a temporal adaptive response occurs in A549 cells as sirtinol enhances transferrin receptor stability and represses ferritin heavy chain translation through impaired aconitase activity and apparent IRP1 activation. This effect was not observed in H1299 cells. Holo-transferrin supplementation significantly enhanced colony formation in A549 cells while increasing sirtinol toxicity. This effect was not observed in H1299 cells. The results highlight the fundamental genetic differences that may exist between H1299 and A549 cells and offer a novel mechanism of how sirtinol kills NSCLC cells.

Cancer Biology

Iron

cancer therapy

iron metabolism

non-small cell lung cancer (NSCLC)

Details

Title: Subtitle: Evaluating the iron chelator function of sirtinol in non-small cell lung cancer
Creators: Michael S. Petronek - University of Iowa
Khaliunaa Bayanbold - University of Iowa
Koffi Amegble - Grinnell College
Ann M. Tomanek-Chalkley - University of Iowa
Bryan G. Allen - University of Iowa
Douglas R. Spitz - University of Iowa
Charvann K. Bailey - Grinnell College
Resource Type: Journal article
Publication Details: Frontiers in oncology, Vol.13, 1185715
DOI: 10.3389/fonc.2023.1185715
PMID: 37397370
PMCID: PMC10313412
NLM abbreviation: Front Oncol
eISSN: 2234-943X
Publisher: Frontiers Media S.A
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: P01 CA217797, P01 CA244091, G-17-1500, P30 CA086862
Language: English
Date published: 06/01/2023
Academic Unit: Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984436279002771

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