ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features

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 (ASHI), 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 ASHI expression by plasmid-based RNA interference (RNAi) to significantly suppress growth of lung cancer cells with ASHI expression through G(2)-M cell cycle arrest and accumulation of sub-G(1) populations, possibly linked to cleavage of caspase-9 and caspase-7. However, lung cancer cell lines without ASHI expression and immortalized normal BEAS2B bronchial epithelial cells were not affected. The RNAi-resistant mutant ASHI clearly induced rescue from G(2)-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 ASHI-RNAi adenovirus. The present study therefore suggests that ASHI plays a crucial role in lung cancer development and may be an effective therapeutic target in lung cancers with neuroendocrine features. (Cancer Res 2005; 65(23): 10680-5).