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Low UBE4B expression increases sensitivity of chemoresistant neuroblastoma cells to EGFR and STAT5 inhibition.

Authors
  • Memarzadeh, Kimiya1
  • Savage, David J1
  • Bean, Andrew J1, 2, 3, 4
  • 1 Program in Neuroscience, University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences , Houston , TX , USA.
  • 2 Department of Neurobiology and Anatomy, McGovern Medical School , Houston , TX , USA.
  • 3 Program in Neuroscience, Cell Biology and Biochemistry, University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences , Houston , TX , USA.
  • 4 Department of Pediatrics, University of Texas MD Anderson Cancer Center , Houston , TX , USA.
Type
Published Article
Journal
Cancer Biology & Therapy
Publisher
Landes Bioscience
Publication Date
Jan 01, 2019
Volume
20
Issue
12
Pages
1416–1429
Identifiers
DOI: 10.1080/15384047.2019.1647049
PMID: 31475882
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Neuroblastoma is the most common malignancy in infants. Overexpression of the epidermal growth factor receptor (EGFR) in neuroblastoma tumors underlies resistance to chemotherapeutics. UBE4B, an E3/E4 ubiquitin ligase involved in EGFR degradation, is located on chromosome 1p36, a region in which loss of heterozygosity is observed in approximately one-third of neuroblastoma tumors and is correlated with poor prognosis. In chemoresistant neuroblastoma cells, depletion of UBE4B yielded significantly reduced cell proliferation and migration, and enhanced apoptosis in response to EGFR inhibitor, Cetuximab. We have previously shown that UBE4B levels are inversely correlated with EGFR levels in neuroblastoma tumors. We searched for additional targets of UBE4B that mediate cellular alterations associated with tumorogenesis in chemoresistant neuroblastoma cells depleted of UBE4B using reverse phase protein arrays. The expression of STAT5a, an effector protein downstream of EGFR, doubled in the absence of UBE4B, and verified by quantitative immunoblotting. Chemoresistant neuroblastoma cells were treated with SH-4-54, a STAT5 inhibitor, and observed insignificant effects on cell proliferation, migration, and apoptosis. However, SH-4-54 significantly enhanced the anti-proliferative and anti-migratory effects of Cetuximab in naïve SK-N-AS neuroblastoma cells. Interestingly, in UBE4B depleted SK-N-AS cells, SH-4-54 significantly potentiated the effect of Cetuximab rendering cells increasingly sensitive an otherwise minimally effective Cetuximab concentration. Thus, neuroblastoma cells with low UBE4B levels were significantly more sensitive to combined EGFR and STAT5 inhibition than parental cells. These findings may have potential therapeutic implications for patients with 1p36 chromosome LOH and low tumor UBE4B expression.

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