ADH5 inhibits proliferation but promotes EMT in non-small cell lung cancer cell through activating Smad2/Smad3.

Abstract

Cell proliferation and epithelial-mesenchymal transition (EMT) are two common tumor phenotypes closely linked to malignant tumor progression. Genes regulating tumor progression often exhibit consistent regulatory trends in these phenotypes; however, certain genes may display inconsistent regulatory patterns in tumor proliferation and EMT. In this investigation, initial transcriptomic and tumor database analyses revealed that alcohol dehydrogenase 5 (ADH5) is downregulated in non-small cell lung cancer (NSCLC) tissues and correlates negatively with NSCLC prognosis. Subsequent experimental manipulation of ADH5 levels in tumor cells demonstrated that ADH5 overexpression decreased proliferation while enhancing migration and invasion capacities in NSCLC cells. Moreover, ADH5 overexpression hindered xenograft tumor growth in nude mice. However, ADH5 knockdown yielded contrasting outcomes by stimulating NSCLC cell proliferation while impeding migration and invasion abilities. Notably, ADH5 overexpression triggered EMT through Smad2/Smad3 activation, leading to the upregulation of SRY-Box Transcription Factor 9. TGFbetaR1/ALK5 inhibitor SB431542 was able to alleviate the effects of ADH5 overexpression on NSCLC cells. This study indicates a critical role of ADH5 in tumors associated with cancer cell growth inhibition but EMT activation. These findings underscore ADH5 as a potential regulator of NSCLC cell plasticity, emphasizing its promise as a therapeutic target for NSCLC management.