Targeting Cyclin D1 in Non-small Cell Lung Cancer and Mesothelioma Cells by Antisense Oligonucleotides

Background: Cyclin D1 overexpression exists in multiple types of cancer and is a potential chemopreventive or therapeutic target. Materials and Methods: Non-small cell lung cancer and mesothelioma cells were incubated with antisense oligonucleotides (ASO) to cyclin D1 (CD1) and evaluated for effects on cellular proliferation, apoptosis, expression of cell cycle-specific proteins, and protein phosphorylation states. Results: ASO to CD1 inhibited proliferation of non-small lung cancer cells and mesothelioma cells. ASO induced apoptosis as determined by TUNEL assay. Western blot analysis of cell lysate showed that ASO inhibited the de novo synthesis of CD1, CD3, and CDK2 in multiple cell lines. Immunoprecipitation and immunoblotting with phosphoantibodies demonstrated that CD1, CD3, and CDK2 exist in a phosphorylated state. Conclusion: The work demonstrates that non-small cell lung cancer and mesothelioma cells respond to ASO-mediated cellular growth inhibition. These findings make ASO to CD1 attractive as a potential therapeutic for mesothelioma and non-small cell lung cancer. Complexes of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors are implicated in the various stages of cell cycle progression in mammalian cells (1). CD1, CD2, and