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
| Autor: | Joerg Dietrich, Tiefei Dong, Margot Mayer-Pröschel, Ibro Ambeskovic, Zaibo Li, Jennifer L. Stripay, Yin Miranda Yang, Ruolan Han, Christopher J. Folts, Brett M. Stevens, Mark Noble, Hsing-Yu Chen, Christoph Pröschel, Wanchang Cui |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
biology
Cell Cancer CDC42 Protein degradation medicine.disease Proto-Oncogene Proteins c-fyn Biochemistry Article Ubiquitin ligase Cell biology medicine.anatomical_structure FYN Physiology (medical) Neoplasms Cancer cell biology.protein medicine Animals Humans Proto-Oncogene Proteins c-cbl Signal transduction Oxidation-Reduction |
| Zdroj: | Free Radic Biol Med |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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