title: Astemizole-Histamine induces Beclin-1-independent autophagy by targeting p53-dependent crosstalk between autophagy and apoptosis.
abstract: Apoptosis and autophagy are genetically regulated, evolutionarily conserved processes that can jointly seal cancer cell fates, and numerous death stimuli are capable of activating either pathway. Although crosstalk between apoptosis and autophagy is quite complex and sometimes contradictory, it remains a key factor determining the outcomes of death-related pathologies such as cancer. In the present study, exposure of MCF-7 breast cancer cells to HIS and the H1 receptor antagonist AST both alone and together with HIS (AST-HIS) led to generation of intracellular ROS, which induced massive cellular vacuolization through dilation of the ER and mitochondria. Consequently, apoptosis by Bax translocation, cytochrome c release, and caspase activation were triggered. In addition, AST-HIS caused ER stress-induced autophagy in MCF-7 cells, as evidenced by an increased LC3-II/LC3-I ratio, with surprisingly no changes in Beclin-1 expression. Non-canonical autophagy was induced via p53 phosphorylation, which increased p53-p62 interactions to enhance Beclin-1-independent autophagy as evidenced by immunocytochemistry and immunoprecipitation. In the absence of Beclin-1, enhanced autophagy further activated apoptosis through caspase induction. In conclusion, these findings indicate that AST-HIS-induced apoptosis and autophagy can be regulated by ROS-mediated signaling pathways.
authors.affiliation: Department of Biotechnology, Daegu University, Kyoungsan, Kyoungbook 712-714, Republic of Korea.
authors.forename: Rekha
authors.initials: R
authors.lastname: Jakhar
authors.affiliation: Department of Biotechnology, Daegu University, Kyoungsan, Kyoungbook 712-714, Republic of Korea.
authors.forename: Souren
authors.initials: S
authors.lastname: Paul
authors.affiliation: Department of Biotechnology, Daegu University, Kyoungsan, Kyoungbook 712-714, Republic of Korea.
authors.forename: Monika
authors.initials: M
authors.lastname: Bhardwaj
authors.affiliation: Department of Biotechnology, Daegu University, Kyoungsan, Kyoungbook 712-714, Republic of Korea. Electronic address: sckang@daegu.ac.kr.
authors.forename: Sun Chul
authors.initials: SC
authors.lastname: Kang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D016589:Astemizole / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D006632:Histamine / Q000494:pharmacology*; D039563:Histamine H1 Antagonists, Non-Sedating / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D039563:Histamine H1 Antagonists, Non-Sedating; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016589:Astemizole; D006632:Histamine; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases
keywords: Apoptosis; Astemizole; ER stress; H1 receptor; Non-canonical autophagy; p53