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Synuclein γ protects Akt and mTOR and renders tumor resistance to Hsp90 disruption

W Liang1, S Miao1, B Zhang1

  • 1Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Oncogene
|June 24, 2014
PubMed

Insights

Synuclein gamma (SNCG) protects Akt and mTOR signaling when heat shock protein 90 (Hsp90) is inhibited, promoting cancer cell survival. SNCG expression in breast cancer correlates with poorer patient outcomes, suggesting it drives drug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Heat shock protein 90 (Hsp90) is a crucial regulator of oncogenic pathways, including Akt and mammalian target of rapamycin (mTOR).
  • Targeting Hsp90 is a promising cancer therapy strategy due to its broad inhibition of oncogenic pathways.

Purpose of the Study:

  • To investigate the role of synuclein gamma (SNCG) in mediating resistance to Hsp90 inhibition.
  • To elucidate the molecular mechanisms by which SNCG affects Akt and mTOR signaling under Hsp90-disrupted conditions.

Main Methods:

  • In vitro and in vivo experiments using cancer cell lines and tumor xenografts.
  • Assessment of Akt and mTOR activity upon Hsp90 inhibition and SNCG expression.
  • Co-immunoprecipitation assays to determine binding interactions between SNCG, Akt, and mTOR.
  • Clinical correlation analysis of SNCG expression with patient survival data.

Main Results:

  • Disruption of Hsp90 abolished Akt and mTOR signaling, but SNCG expression restored their activity.
  • SNCG directly bound to Akt and mTOR, independent of Hsp90.
  • SNCG conferred resistance to 17-AAG-induced apoptosis in vitro and in vivo.
  • SNCG-positive breast cancer patients exhibited significantly shorter disease-free and overall survival.

Conclusions:

  • SNCG protects Hsp90 client proteins Akt and mTOR, thereby conferring resistance to Hsp90-targeting drugs.
  • SNCG is a potential biomarker for predicting poor prognosis and drug resistance in breast cancer.

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