Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells.

Details

Serval ID
serval:BIB_A76A436E8778
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Genini D., Brambilla L., Laurini E., Merulla J., Civenni G., Pandit S., D'Antuono R., Perez L., Levy D.E., Pricl S., Carbone G.M., Catapano C.V.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
20/06/2017
Peer-reviewed
Oui
Volume
114
Number
25
Pages
E4924-E4933
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
In addition to its canonical role in nuclear transcription, signal transducer and activator of transcription 3 (STAT3) is emerging as an important regulator of mitochondrial function. Here, we demonstrate that a novel inhibitor that binds with high affinity to the STAT3 SH2 domain triggers a complex cascade of events initiated by interference with mitochondrial STAT3 (mSTAT3). The mSTAT3-drug interaction leads to mitochondrial dysfunction, accumulation of proteotoxic STAT3 aggregates, and cell death. The cytotoxic effects depend directly on the drug's ability to interfere with mSTAT3 and mitochondrial function, as demonstrated by site-directed mutagenesis and use of STAT3 knockout and mitochondria-depleted cells. Importantly, the lethal consequences of mSTAT3 inhibition are enhanced by glucose starvation and by increased reliance of cancer cells and tumor-initiating cells on mitochondria, resulting in potent activity in cell cultures and tumor xenografts in mice. These findings can be exploited for eliciting synthetic lethality in metabolically stressed cancer cells using high-affinity STAT3 inhibitors. Thus, this study provides insights on the role of mSTAT3 in cancer cells and a conceptual framework for developing more effective cancer therapies.
Keywords
Animals, Cell Death/genetics, Cell Line, Tumor, Humans, Male, Mice, Mice, Nude, Mitochondria/genetics, Neoplasms/genetics, STAT3 Transcription Factor/genetics, Synthetic Lethal Mutations/genetics, src Homology Domains/genetics, OPB-51602, STAT3, mitochondria, small-molecule inhibitor, synthetic lethality
Pubmed
Web of science
Open Access
Yes
Create date
13/06/2017 19:17
Last modification date
20/08/2019 15:12
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