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

Debra Akin1, S Keisin Wang, Pouran Habibzadegah-Tari

  • 1a Department of Anatomy and Cell Biology ; University of Florida ; Gainesville , FL USA.

Autophagy
|December 9, 2014
PubMed

Insights

Targeting ATG4B, a key autophagy protein, inhibits osteosarcoma tumor growth. Suppressing autophagy via ATG4B antagonism offers a potential therapeutic strategy for osteosarcoma treatment.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Autophagy plays a role in cancer progression and chemoresistance.
  • Osteosarcoma progression and treatment resistance are linked to autophagy.
  • ATG4B is a critical enzyme for autophagy, activating LC3B.

Purpose of the Study:

  • To investigate the role of ATG4B in osteosarcoma.
  • To identify small molecule inhibitors of ATG4B.
  • To evaluate ATG4B inhibition as a therapeutic strategy for osteosarcoma.

Main Methods:

  • In silico docking, in vitro assays, and cell-based assays were used to identify ATG4B inhibitors.
  • Osteosarcoma Saos-2 cells and mouse models were utilized.
  • Inhibition of autophagy markers (protein degradation, LC3B lipidation, autophagic vacuoles) and tumor growth were assessed.

Main Results:

  • Osteosarcoma cells lacking ATG4B were defective in autophagy and did not form tumors in mice.
  • NSC185058 was identified as an ATG4B inhibitor, suppressing autophagy markers without affecting MTOR or PtdIns3K.
  • Treatment with NSC185058 inhibited osteosarcoma tumor development in vivo.

Conclusions:

  • ATG4B is essential for osteosarcoma tumor formation.
  • Targeting ATG4B with small molecule inhibitors suppresses osteosarcoma growth.
  • ATG4B is a promising therapeutic target for osteosarcoma treatment.
Keywords:
3MA, 3-methyladenineACTB, actin, betaATG, autophagy-relatedATG4BATG4B, autophagy-related 4B, cysteine proteaseAV, autophagic vacuoleBECN1, beclin 1, autophagy relatedCMPase, cytidine monophosphataseDMEM, Dulbecco's modified Eagle mediumECL, enhanced chemiluminescenceFYVE, zinc-finger domain named after 4 cysteine-rich proteins: FAB1, YOTB, VAC1, and EEA1GABARAPL2, GABA(A) receptor-associated protein-like 2GFP, green fluorescent proteinGST, glutathione S-transferaseHRP, horseradish peroxidaseIC50, half maximal inhibitory concentrationIP, intraperitonealLC3BMAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3betaMP, melting pointMTOR, mechanistic target of rapamycinNCI, National Cancer InstituteNMR, nuclear magnetic resonancePLA2, phospholipase A2PVDF, polyvinylidene difluoridePtdIns3K, phosphatidylinositol 3-kinase class IIIPtdIns3P, phosphatidylinositol 3-phosphateRFP, red fluorescent proteinRLU, relative luciferase unitsRPS6, ribosomal protein S6RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1SEM, standard error of the meanULK1/2, unc-51-like autophagy activating kinase 1/2and xenograftsantiautophagy compoundsdNGLUC, Gaussia luciferasein silico dockingosteosarcoma

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