A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors

Debra Akin, S. Keisin Wang, Pouran Habibzadegah-Tari, Brian Law, David Ostrov, Min Li, Xiao-Ming Yin, Jae Sung Kim, Nicole Horenstein, William A. Dunn

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Autophagy has been implicated in the progression and chemoresistance of various cancers. In this study, we have shown that osteosarcoma Saos-2 cells lacking ATG4B, a cysteine proteinase that activates LC3B, are defective in autophagy and fail to form tumors in mouse models. By combining in silico docking with in vitro and cell-based assays, we identified small compounds that suppressed starvation-induced protein degradation, LC3B lipidation, and formation of autophagic vacuoles. NSC185058 effectively inhibited ATG4B activity in vitro and in cells while having no effect on MTOR and PtdIns3K activities. In addition, this ATG4B antagonist had a negative impact on the development of Saos-2 osteosarcoma tumors in vivo. We concluded that tumor suppression was due to a reduction in ATG4B activity, since we found autophagy suppressed within treated tumors and the compound had no effects on oncogenic protein kinases. Our findings demonstrate that ATG4B is a suitable anti-autophagy target and a promising therapeutic target to treat osteosarcoma.

Original languageEnglish
Pages (from-to)2021-2035
Number of pages15
JournalAutophagy
Volume10
Issue number11
DOIs
StatePublished - Nov 1 2014

Fingerprint

Autophagy
Osteosarcoma
Neoplasms
Cysteine Proteases
Starvation
Vacuoles
Computer Simulation
Protein Kinases
Proteolysis
In Vitro Techniques
Therapeutics

Keywords

  • Antiautophagy compounds
  • ATG4B
  • In silico docking
  • LC3B
  • Osteosarcoma
  • Xenografts

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Akin, D., Wang, S. K., Habibzadegah-Tari, P., Law, B., Ostrov, D., Li, M., ... Dunn, W. A. (2014). A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy, 10(11), 2021-2035. https://doi.org/10.4161/auto.32229

A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. / Akin, Debra; Wang, S. Keisin; Habibzadegah-Tari, Pouran; Law, Brian; Ostrov, David; Li, Min; Yin, Xiao-Ming; Kim, Jae Sung; Horenstein, Nicole; Dunn, William A.

In: Autophagy, Vol. 10, No. 11, 01.11.2014, p. 2021-2035.

Research output: Contribution to journalArticle

Akin, D, Wang, SK, Habibzadegah-Tari, P, Law, B, Ostrov, D, Li, M, Yin, X-M, Kim, JS, Horenstein, N & Dunn, WA 2014, 'A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors', Autophagy, vol. 10, no. 11, pp. 2021-2035. https://doi.org/10.4161/auto.32229
Akin D, Wang SK, Habibzadegah-Tari P, Law B, Ostrov D, Li M et al. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy. 2014 Nov 1;10(11):2021-2035. https://doi.org/10.4161/auto.32229
Akin, Debra ; Wang, S. Keisin ; Habibzadegah-Tari, Pouran ; Law, Brian ; Ostrov, David ; Li, Min ; Yin, Xiao-Ming ; Kim, Jae Sung ; Horenstein, Nicole ; Dunn, William A. / A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. In: Autophagy. 2014 ; Vol. 10, No. 11. pp. 2021-2035.
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