title: Synuclein γ protects Akt and mTOR and renders tumor resistance to Hsp90 disruption.
abstract: Heat shock protein (Hsp)90 regulates many key pathways in oncogenesis, including Akt and mammalian target of rapamycin (mTOR). The strengths of disruption of Hsp90 in cancer therapy include their versatility in inhibiting a wide range of oncogenic pathways. The present study demonstrated that synuclein γ (SNCG) protects the functions of Akt and mTOR in the condition when the function of Hsp90 is blocked. Disruption of Hsp90 abolished Akt activity and mTOR signaling. However, expression of SNCG restored Akt activity and mTOR signaling. SNCG bound to Akt and mTOR in the presence and absence of Hsp90. Specifically, the C-terminal (Gln106-Asp127) of SNCG bound to the loop connecting αC helix and β4 sheet of the kinase domain of Akt. SNCG renders resistance to 17-AAG-induced apoptosis both in vitro and in tumor xenograft. A clinical follow-up study indicates that patients with an SNCG-positive breast cancer have a significantly shorter disease-free survival and overall survival than patients with SNCG-negative tumors. The present study indicates that SNCG protects Hsp90 client proteins of Akt and mTOR, and renders drug resistance to Hsp90 disruption.
authors: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors: W
authors: W
authors: Liang
authors: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors: S
authors: S
authors: Miao
authors: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors: B
authors: B
authors: Zhang
authors: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors: S
authors: S
authors: He
authors: Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, China.
authors: C
authors: C
authors: Shou
authors: Centre for Bioinformatics, School of Life Science, Pondicherry University, Puducherry, India.
authors: P
authors: P
authors: Manivel
authors: Centre for Bioinformatics, School of Life Science, Pondicherry University, Puducherry, India.
authors: R
authors: R
authors: Krishna
authors: Department of Surgery, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors: Y
authors: Y
authors: Chen
authors: 1] Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China [2] State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
authors: Y E
authors: YE
authors: Shi
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D056004:Molecular Dynamics Simulation; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D051845:gamma-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009363:Neoplasm Proteins; C104249:SNCG protein, human; D051845:gamma-Synuclein; C112765:tanespimycin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases