Imperial College London
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ProfessorSimoneDi Giovanni

Faculty of Medicine, Department of Brain Sciences

James W Harnett Chair in Restorative Neuroscience
 
 
 
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Contact

 

+44 (0)20 7594 3178s.di-giovanni

 
 
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Location

 

E505Burlington DanesHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Noble:2015:10.1016/j.freeradbiomed.2014.10.860,
author = {Noble, M and Mayer-Pröschel, M and Li, Z and Dong, T and Cui, W and Pröschel, C and Ambeskovic, I and Dietrich, J and Han, R and Yang, YM and Folts, C and Stripay, J and Chen, H-Y and Stevens, BM},
doi = {10.1016/j.freeradbiomed.2014.10.860},
journal = {Free Radic Biol Med},
pages = {300--323},
title = {Redox biology in normal cells and cancer: restoring function of the redox/Fyn/c-Cbl pathway in cancer cells offers new approaches to cancer treatment.},
url = {http://dx.doi.org/10.1016/j.freeradbiomed.2014.10.860},
volume = {79},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - This review discusses a unique discovery path starting with novel findings on redox regulation of precursor cell and signaling pathway function and identification of a new mechanism by which relatively small changes in redox status can control entire signaling networks that regulate self-renewal, differentiation, and survival. The pathway central to this work, the redox/Fyn/c-Cbl (RFC) pathway, converts small increases in oxidative status to pan-activation of the c-Cbl ubiquitin ligase, which controls multiple receptors and other proteins of central importance in precursor cell and cancer cell function. Integration of work on the RFC pathway with attempts to understand how treatment with systemic chemotherapy causes neurological problems led to the discovery that glioblastomas (GBMs) and basal-like breast cancers (BLBCs) inhibit c-Cbl function through altered utilization of the cytoskeletal regulators Cool-1/βpix and Cdc42, respectively. Inhibition of these proteins to restore normal c-Cbl function suppresses cancer cell division, increases sensitivity to chemotherapy, disrupts tumor-initiating cell (TIC) activity in GBMs and BLBCs, controls multiple critical TIC regulators, and also allows targeting of non-TICs. Moreover, these manipulations do not increase chemosensitivity or suppress division of nontransformed cells. Restoration of normal c-Cbl function also allows more effective harnessing of estrogen receptor-α (ERα)-independent activities of tamoxifen to activate the RFC pathway and target ERα-negative cancer cells. Our work thus provides a discovery strategy that reveals mechanisms and therapeutic targets that cannot be deduced by standard genetics analyses, which fail to reveal the metabolic information, isoform shifts, protein activation, protein complexes, and protein degradation critical to our discoveries.
AU  - Noble,M
AU  - Mayer-Pröschel,M
AU  - Li,Z
AU  - Dong,T
AU  - Cui,W
AU  - Pröschel,C
AU  - Ambeskovic,I
AU  - Dietrich,J
AU  - Han,R
AU  - Yang,YM
AU  - Folts,C
AU  - Stripay,J
AU  - Chen,H-Y
AU  - Stevens,BM
DO  - 10.1016/j.freeradbiomed.2014.10.860
EP  - 323
PY  - 2015///
SP  - 300
TI  - Redox biology in normal cells and cancer: restoring function of the redox/Fyn/c-Cbl pathway in cancer cells offers new approaches to cancer treatment.
T2  - Free Radic Biol Med
UR  - http://dx.doi.org/10.1016/j.freeradbiomed.2014.10.860
UR  - https://www.ncbi.nlm.nih.gov/pubmed/25481740
VL  - 79
ER  -
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