Metadherin enhances vulnerability of cancer cells to ferroptosis

Jianling Bi; Shujie Yang; Long Li; Qun Dai; Nicholas Borcherding; Brett A Wagner; Garry R Buettner; Douglas R Spitz; Kimberly K Leslie; Jun Zhang; Xiangbing Meng

doi:10.1038/s41419-019-1897-2

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Metadherin enhances vulnerability of cancer cells to ferroptosis

Journal article

Open access

Peer reviewed

Metadherin enhances vulnerability of cancer cells to ferroptosis

Jianling Bi, Shujie Yang, Long Li, Qun Dai, Nicholas Borcherding, Brett A Wagner, Garry R Buettner, Douglas R Spitz, Kimberly K Leslie, Jun Zhang, …

Cell death & disease, Vol.10(10), pp.682-14

09/17/2019

DOI: 10.1038/s41419-019-1897-2

PMCID: PMC6746770

PMID: 31527591

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Abstract

Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death driven by lipid hydroperoxides within biological membranes. Although therapy-resistant mesenchymal-high cancers are particularly vulnerable to ferroptosis inducers, especially phospholipid glutathione peroxidase 4 (GPx4) inhibitors, the underlying mechanism is yet to be deciphered. As such, the full application of GPx4 inhibitors in cancer therapy remains challenging. Here we demonstrate that metadherin (MTDH) confers a therapy-resistant mesenchymal-high cell state and enhanced sensitivity to inducers of ferroptosis. Mechanistically, MTDH inhibited GPx4, as well as the solute carrier family 3 member 2 (SLC3A2, a system X heterodimerization partner), at both the messenger RNA and protein levels. Our metabolomic studies demonstrated that MTDH reduced intracellular cysteine, but increased glutamate levels, ultimately decreasing levels of glutathione and setting the stage for increased vulnerability to ferroptosis. Finally, we observed an enhanced antitumor effect when we combined various ferroptosis inducers both in vitro and in vivo; the level of MTDH correlated with the ferroptotic effect. We have demonstrated for the first time that MTDH enhances the vulnerability of cancer cells to ferroptosis and may serve as a therapeutic biomarker for future ferroptosis-centered cancer therapy.

Biomarkers, Tumor

Cell Death - drug effects

Cell Line, Tumor

Ferroptosis - genetics

Humans

Membrane Proteins - metabolism

Neoplasms - drug therapy

RNA-Binding Proteins - metabolism

Details

Title: Subtitle: Metadherin enhances vulnerability of cancer cells to ferroptosis
Creators: Jianling Bi - Department of Obstetrics and Gynecology, Iowa City, IA, 52242, USA.
Shujie Yang - Department of Pathology, Iowa City, IA, 52242, USA.
Long Li - Department of Obstetrics and Gynecology, Iowa City, IA, 52242, USA.
Qun Dai - University of Kansas
Nicholas Borcherding - Holden Comprehensive Cancer Center, Iowa City, IA, 52242, USA.
Brett A Wagner - University of Iowa
Garry R Buettner - University of Iowa
Douglas R Spitz - University of Iowa
Kimberly K Leslie - Department of Obstetrics and Gynecology, Iowa City, USA
Jun Zhang - University of Kansas
Xiangbing Meng - Department of Obstetrics and Gynecology, Iowa City, USA
Resource Type: Journal article
Publication Details: Cell death & disease, Vol.10(10), pp.682-14
DOI: 10.1038/s41419-019-1897-2
PMID: 31527591
PMCID: PMC6746770
NLM abbreviation: Cell Death Dis
ISSN: 2041-4889
eISSN: 2041-4889
Grant note: P01 CA217797 / NCI NIH HHS T32 GM007337 / NIGMS NIH HHS R37 CA238274 / NCI NIH HHS F30 CA206255 / NCI NIH HHS R01 CA184101 / NCI NIH HHS R01 CA182804 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA169046 / NCI NIH HHS P50 CA174521 / NCI NIH HHS
Language: English
Date published: 09/17/2019
Academic Unit: Dermatology; Pathology; Radiation Oncology; Obstetrics and Gynecology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984186502402771

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