Tropolone-induced effects on the unfolded protein response pathway and apoptosis in multiple myeloma cells are dependent on iron

Staci L. Haney, Michelle L. Varney, Hannah R. Safranek, Yashpal S. Chhonker, Narendran G-Dayanandan, Geoffrey A Talmon, Daryl J Murry, Andrew J. Wiemer, Dennis L. Wright, Sarah A Holstein

Research output: Contribution to journalArticle

Abstract

Tropolones are naturally occurring seven-membered non-benzenoid aromatic compounds that are of interest due to their cytotoxic properties. MO-OH-Nap is a novel α-substituted tropolone that induces caspase cleavage and upregulates markers associated with the unfolded protein response (UPR) in multiple myeloma (MM) cells. Given previous reports that tropolones may function as iron chelators, we investigated the effects of MO-OH-Nap, as well as the known iron chelator deferoxamine (DFO), in MM cells in the presence or absence of supplemental iron. The ability of MO-OH-Nap to induce apoptosis and upregulate markers of the UPR could be completely prevented by co-incubation with either ferric chloride or ammonium ferrous sulfate. Iron also completely prevented the decrease in BrdU incorporation induced by either DFO or MO-OH-Nap. Ferrozine assays demonstrated that MO-OH-Nap directly chelates iron. Furthermore, MO-OH-Nap upregulates cell surface expression and mRNA levels of transferrin receptor. In vivo studies demonstrate increased Prussian blue staining in hepatosplenic macrophages in MO-OH-Nap-treated mice. These studies demonstrate that MO-OH-Nap-induced cytotoxic effects in MM cells are dependent on the tropolone's ability to alter cellular iron availability and establish new connections between iron homeostasis and the UPR in MM.

Original languageEnglish (US)
Pages (from-to)17-27
Number of pages11
JournalLeukemia Research
Volume77
DOIs
StatePublished - Feb 1 2019

Fingerprint

Tropolone
Unfolded Protein Response
Multiple Myeloma
Iron
Apoptosis
Deferoxamine
Up-Regulation
Chelating Agents
Ferrozine
Iron Chelating Agents
Transferrin Receptors
hydroxide ion
Bromodeoxyuridine
Caspases
Homeostasis
Macrophages
Staining and Labeling
Messenger RNA

Keywords

  • Apoptosis
  • Iron
  • Multiple myeloma
  • Tropolone
  • Unfolded protein response pathway

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Tropolone-induced effects on the unfolded protein response pathway and apoptosis in multiple myeloma cells are dependent on iron. / Haney, Staci L.; Varney, Michelle L.; Safranek, Hannah R.; Chhonker, Yashpal S.; G-Dayanandan, Narendran; Talmon, Geoffrey A; Murry, Daryl J; Wiemer, Andrew J.; Wright, Dennis L.; Holstein, Sarah A.

In: Leukemia Research, Vol. 77, 01.02.2019, p. 17-27.

Research output: Contribution to journalArticle

Haney, Staci L. ; Varney, Michelle L. ; Safranek, Hannah R. ; Chhonker, Yashpal S. ; G-Dayanandan, Narendran ; Talmon, Geoffrey A ; Murry, Daryl J ; Wiemer, Andrew J. ; Wright, Dennis L. ; Holstein, Sarah A. / Tropolone-induced effects on the unfolded protein response pathway and apoptosis in multiple myeloma cells are dependent on iron. In: Leukemia Research. 2019 ; Vol. 77. pp. 17-27.
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AU - Chhonker, Yashpal S.

AU - G-Dayanandan, Narendran

AU - Talmon, Geoffrey A

AU - Murry, Daryl J

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AU - Wright, Dennis L.

AU - Holstein, Sarah A

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AB - Tropolones are naturally occurring seven-membered non-benzenoid aromatic compounds that are of interest due to their cytotoxic properties. MO-OH-Nap is a novel α-substituted tropolone that induces caspase cleavage and upregulates markers associated with the unfolded protein response (UPR) in multiple myeloma (MM) cells. Given previous reports that tropolones may function as iron chelators, we investigated the effects of MO-OH-Nap, as well as the known iron chelator deferoxamine (DFO), in MM cells in the presence or absence of supplemental iron. The ability of MO-OH-Nap to induce apoptosis and upregulate markers of the UPR could be completely prevented by co-incubation with either ferric chloride or ammonium ferrous sulfate. Iron also completely prevented the decrease in BrdU incorporation induced by either DFO or MO-OH-Nap. Ferrozine assays demonstrated that MO-OH-Nap directly chelates iron. Furthermore, MO-OH-Nap upregulates cell surface expression and mRNA levels of transferrin receptor. In vivo studies demonstrate increased Prussian blue staining in hepatosplenic macrophages in MO-OH-Nap-treated mice. These studies demonstrate that MO-OH-Nap-induced cytotoxic effects in MM cells are dependent on the tropolone's ability to alter cellular iron availability and establish new connections between iron homeostasis and the UPR in MM.

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