title: ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features.
abstract: Lung cancers with neuroendocrine features are usually aggressive, although the underlying molecular mechanisms largely remain to be determined. The basic helix-loop-helix protein, achaete-scute complex-like 1/achaete-scute homologue 1 (ASH1), is expressed in normal fetal pulmonary neuroendocrine cells and lung cancers with neuroendocrine elements and is suggested to be involved in lung carcinogenesis. In the present study, we show inhibition of ASH1 expression by plasmid-based RNA interference (RNAi) to significantly suppress growth of lung cancer cells with ASH1 expression through G2-M cell cycle arrest and accumulation of sub-G1 populations, possibly linked to cleavage of caspase-9 and caspase-7. However, lung cancer cell lines without ASH1 expression and immortalized normal BEAS2B bronchial epithelial cells were not affected. The RNAi-resistant mutant ASH1 clearly induced rescue from G2-M arrest, suggesting a target-specific effect of RNAi. An ASH1-RNAi adenovirus was also established and significantly inhibited not only in vitro cell proliferation but also in vivo xenograft growth of ASH1-positive NCI-H460 cells. Elevated levels of apoptosis were also observed in NCI-H460 xenografts with the ASH1-RNAi adenovirus. The present study therefore suggests that ASH1 plays a crucial role in lung cancer development and may be an effective therapeutic target in lung cancers with neuroendocrine features.
authors.affiliation: Division of Molecular Oncology, Aichi Cancer Center Research Institute, Chikusa, Nagoya, Japan. hosada@aichi-cc.jp
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Osada
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Tatematsu
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Horio
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D016195:G2 Phase / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D034622:RNA Interference; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C065500:ASCL1 protein, human