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.
abstract: 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.
authors.affiliation: Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: mark_noble@urmc.rochester.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Noble
authors.affiliation: Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: margot_mayer-proschel@urmc.rochester.edu.
authors.forename: Margot
authors.initials: M
authors.lastname: Mayer-Pröschel
authors.affiliation: Department of Pathology, Ohio State University Wexner Medical Center, 410W 10th Avenue, E403 Doan Hall, Columbus, OH 43210-1240, USA. Electronic address: liz2@upmc.edu.
authors.forename: Zaibo
authors.initials: Z
authors.lastname: Li
authors.affiliation: University of Michigan Tech Transfer, 1600 Huron Pkwy, 2nd Floor, Building 520, Ann Arbor, MI 48109-2590, USA. Electronic address: tiefeid@umich.edu.
authors.forename: Tiefei
authors.initials: T
authors.lastname: Dong
authors.affiliation: Department of Radiation Oncology, University of Maryland School of Medicine,10 South Pine Street, MSTF Room 600, Baltimore, MD 21201, USA. Electronic address: wcui@som.umaryland.edu.
authors.forename: Wanchang
authors.initials: W
authors.lastname: Cui
authors.affiliation: Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: Chris_Proschel@urmc.rochester.edu.
authors.forename: Christoph
authors.initials: C
authors.lastname: Pröschel
authors.affiliation: Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: Ibro_Ambeskovic@URMC.Rochester.edu.
authors.forename: Ibro
authors.initials: I
authors.lastname: Ambeskovic
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Yawkey 9E, Boston, MA 02114, USA. Electronic address: joergdietrich@hotmail.com.
authors.forename: Joerg
authors.initials: J
authors.lastname: Dietrich
authors.affiliation: Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: ruolan.han@gmail.com.
authors.forename: Ruolan
authors.initials: R
authors.lastname: Han
authors.affiliation: Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: yyang607@gmail.com.
authors.forename: Yin Miranda
authors.initials: YM
authors.lastname: Yang
authors.affiliation: Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: Christopher_Folts@URMC.Rochester.edu.
authors.forename: Christopher
authors.initials: C
authors.lastname: Folts
authors.affiliation: Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: Jennifer_Stripay@URMC.Rochester.edu.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stripay
authors.affiliation: Harvard Medical School, Department of Cell Biology 240 Longwood Avenue Building C1, Room 513B Boston, MA 02115, USA. Electronic address: hsing-yu_chen@hms.harvard.edu.
authors.forename: Hsing-Yu
authors.initials: HY
authors.lastname: Chen
authors.affiliation: University of Colorado School of Medicine, Division of Hematology, 12700 E. 19th Avenue, Campus Box F754-AMCA, Aurora, CO 80045, USA. Electronic address: brett.stevens@ucdenver.edu.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Stevens
mesh_terms: D000818:Animals; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D010084:Oxidation-Reduction; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*
chemical_list: D050721:Proto-Oncogene Proteins c-cbl; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; C067419:CBL protein, human
keywords: Basal-like breast cancer; Glioblastoma; Oligodendrocyte/type-2 astrocyte progenitor cell; Progenitor cell; Redox; Redox/Fyn/c-Cbl pathway; Stem cell; Tamoxifen; Tumor initiating cell; c-Cbl