title: Autophagy inhibition enhances apoptosis triggered by BO-1051, an N-mustard derivative, and involves the ATM signaling pathway.
abstract: In a previous study, BO-1051, an N-mustard linked with a DNA-affinic molecule, was shown to target various types of cancer cell lines. In the present study, we aimed to investigate the cytotoxicity, as well as the underlying mechanism, of BO-1051. We found that BO-1051 simultaneously induced apoptosis and autophagy in hepatocellular carcinoma cell lines. DNA double strand breaks induced by BO-1051 activated the ATM signaling pathway and subsequently resulted in caspase-dependent apoptosis. When autophagy was inhibited in its early or late stages, apoptosis was significantly enhanced. This result indicated autophagy as a cytoprotective effect against BO-1051-induced cell death. We further inhibited ATM activation using an ATM kinase inhibitor or ATM-specific siRNA and found that while apoptosis was blocked, autophagy also diminished in response to BO-1051. We not only determined a signaling pathway induced by BO-1051 but also clarified the linkage between DNA damage-induced apoptosis and autophagy. We also showed that BO-1051-induced autophagy acts as a cytoprotective reaction and downstream target of the ATM-signaling pathway. This research revealed autophagy as a universal cytoprotective response against DNA damage-inducing chemotherapeutic agents, including BO-1051, cisplatin, and doxorubicin, in hepatocellular carcinoma cell lines. Autophagy contributes to the remarkable drug resistance ability of liver cancer.
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, 155, Sec 2, Linong Street, Taipei 112, Taiwan.
authors.forename: Li-Hsin
authors.initials: LH
authors.lastname: Chen
authors.forename: Che-Chuan
authors.initials: CC
authors.lastname: Loong
authors.forename: Tsann-Long
authors.initials: TL
authors.lastname: Su
authors.forename: Yi-Jang
authors.initials: YJ
authors.lastname: Lee
authors.forename: Pei-Ming
authors.initials: PM
authors.lastname: Chu
authors.forename: Ming-Long
authors.initials: ML
authors.lastname: Tsai
authors.forename: Ping-Hsin
authors.initials: PH
authors.lastname: Tsai
authors.forename: Pang-Hsien
authors.initials: PH
authors.lastname: Tu
authors.forename: Chin-Wen
authors.initials: CW
authors.lastname: Chi
authors.forename: Hsin-Chen
authors.initials: HC
authors.lastname: Lee
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D001343:Autophagy / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular; D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; C557045:BO-1051; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009588:Nitrogen Mustard Compounds; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases