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 Miller, Hong-Gang Wang

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 1 2018

Fingerprint

Autophagy
Neuroblastoma
Apoptosis
Neoplasm Metastasis
Growth
Neoplasms
Topoisomerase Inhibitors
Topotecan
Autophagy-Related Protein-1 Homolog
Heterografts
Doxorubicin
Cell Survival
Phosphotransferases
Therapeutics
Pediatrics
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Dower, Christopher M. ; Bhat, Neema ; Gebru, Melat T. ; Chen, Longgui ; Wills, Carson A. ; Miller, Barbara ; Wang, Hong-Gang. / Targeted inhibition of ULK1 promotes apoptosis and suppresses tumor growth and metastasis in neuroblastoma. In: Molecular cancer therapeutics. 2018 ; Vol. 17, No. 11. pp. 2365-2376.
@article{cdb4cb68c2a34922bb06b34f51cdd3bf,
title = "Targeted inhibition of ULK1 promotes apoptosis and suppresses tumor growth and metastasis in neuroblastoma",
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.",
author = "Dower, {Christopher M.} and Neema Bhat and Gebru, {Melat T.} and Longgui Chen and Wills, {Carson A.} and Barbara Miller and Hong-Gang Wang",
year = "2018",
month = "11",
day = "1",
doi = "10.1158/1535-7163.MCT-18-0176",
language = "English (US)",
volume = "17",
pages = "2365--2376",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "11",

}

Targeted inhibition of ULK1 promotes apoptosis and suppresses tumor growth and metastasis in neuroblastoma. / Dower, Christopher M.; Bhat, Neema; Gebru, Melat T.; Chen, Longgui; Wills, Carson A.; Miller, Barbara; Wang, Hong-Gang.

In: Molecular cancer therapeutics, Vol. 17, No. 11, 01.11.2018, p. 2365-2376.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Targeted inhibition of ULK1 promotes apoptosis and suppresses tumor growth and metastasis in neuroblastoma

AU - Dower, Christopher M.

AU - Bhat, Neema

AU - Gebru, Melat T.

AU - Chen, Longgui

AU - Wills, Carson A.

AU - Miller, Barbara

AU - Wang, Hong-Gang

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85055911632&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055911632&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-18-0176

DO - 10.1158/1535-7163.MCT-18-0176

M3 - Article

C2 - 30166400

AN - SCOPUS:85055911632

VL - 17

SP - 2365

EP - 2376

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 11

ER -