title: Suberoylanilide hydroxamic acid (SAHA) causes tumor growth slowdown and triggers autophagy in glioblastoma stem cells.
abstract: Although suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has been used in clinical trials for cancer therapies, its pharmacological effects occur through a poorly understood mechanism. Here, we report that SAHA specifically triggers autophagy and reduces cell viability via promotion of apoptosis in the late phase of glioblastoma stem cells (GSCs). Using a cell line cultured from a glioblastoma biopsy, we investigated the properties and effects of GSCs under SAHA treatment in vitro. In vivo xenograft assays revealed that SAHA effectively caused tumor growth slowdown and the induction of autophagy. SAHA was sufficient to increase formation of intracellular acidic vesicle organelles, recruitment of LC3-II to the autophagosomes, potentiation of BECN1 protein levels and reduced SQSTM1 levels. We determined that SAHA triggered autophagy through the downregulation of AKT-MTOR signaling, a major suppressive cascade of autophagy. Interestingly, upon depletion or pharmacological inhibition of autophagy, SAHA facilitates apoptosis and results in cell death at the early phase, suggesting that SAHA-induced autophagy functions probably act as a prosurvival mechanism. Furthermore, our results also indicated that the inhibition of SAHA-induced autophagy using chloroquine has synergistic effects that further increase apoptosis. Moreover, we found that a reduced dose of SAHA functioned as a potent modulator of differentiation and senescence. Taken together, our results provide a new perspective on the treatment of GSCs, indicating that SAHA is a promising agent for targeting GSCs through the induction of autophagy.
authors: Institute of Medicine; Chung Shan Medical University; Taichung, Taiwan; Institute of Medical and Molecular Toxicology; Chung Shan Medical University; Taichung, Taiwan.
authors: Ming-Tsang
authors: MT
authors: Chiao
authors: Department of Neurosurgery; Taichung Veterans General Hospital; Taichung, Taiwan.
authors: Wen-Yu
authors: WY
authors: Cheng
authors: Department of Neurosurgery; Taichung Veterans General Hospital; Taichung, Taiwan.
authors: Yi-Chin
authors: YC
authors: Yang
authors: Department of Neurosurgery; Taichung Veterans General Hospital; Taichung, Taiwan; Department of Medicine; National Defense Medical Center; Taipei, Taiwan; Tri-Service General Hospital; National Defense Medical Center; Taipei, Taiwan; Department of Physical Therapy; Hungkuang University; Taichung, Taiwan.
authors: Chiung-Chyi
authors: CC
authors: Shen
authors: Institute of Medicine; Chung Shan Medical University; Taichung, Taiwan; Institute of Medical and Molecular Toxicology; Chung Shan Medical University; Taichung, Taiwan; Department of Medical Oncology; Chung Shan Medical University Hospital; Taichung, Taiwan; Lung Cancer Research Center; Institute of Medicine; Chung Shan Medical University Hospital; Taichung, Taiwan.
authors: Jiunn-Liang
authors: JL
authors: Ko
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects*; D010588:Phagosomes / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat
keywords: AKT-MTOR signaling; SAHA; autophagy; chloroquine; glioblastoma stem cells