Targeted inhibition of ULK1 promotes apoptosis and suppresses tumor growth and metastasis in neuroblastoma

Christopher M. Dower, Neema Bhat, Melat T. Gebru, Longgui Chen, Carson A. Wills, Barbara A. Miller, Hong Gang Wang

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Neuroblastoma is the most common extracranial solid malignancy in the pediatric population, accounting for over 9% of all cancer-related deaths in children. Autophagy is a cell self-protective mechanism that promotes tumor cell growth and survival, making it an attractive target for treating cancer. However, the role of autophagy in neuroblastoma tumor growth and metastasis is largely undefined. Here we demonstrate that targeted inhibition of an essential autophagy kinase, unc-51 like autophagy kinase 1 (ULK1), with a recently developed small-molecule inhibitor of ULK1, SBI-0206965, significantly reduces cell growth and promotes apoptosis in SK-NAS, SH-SY5Y, and SK-N-DZ neuroblastoma cell lines. Furthermore, inhibition of ULK1 by a dominant-negative mutant of ULK1 (dnULK1 K46N ) significantly reduces growth and metastatic disease and prolongs survival of mice bearing SK-N-AS xenograft tumors. We also show that SBI-0206965 sensitizes SKN-AS cells to TRAIL treatment, but not to mTOR inhibitors (INK128, Torin1) or topoisomerase inhibitors (doxorubicin, topotecan). Collectively, these findings demonstrate that ULK1 is a viable drug target and suggest that inhibitors of ULK1 may provide a novel therapeutic option for the treatment of neuroblastoma.

Original languageEnglish (US)
Pages (from-to)2365-2376
Number of pages12
JournalMolecular cancer therapeutics
Volume17
Issue number11
DOIs
StatePublished - Nov 2018

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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