Nattanan Losuwannarak1,2, Sittiruk Roytrakul3, Pithi Chanvorachote4,2. 1. Cell-Based Drug and Health Product Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand. 2. Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand. 3. Functional Ingredients and Food Innovation Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathumthani, Thailand. 4. Cell-Based Drug and Health Product Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand pithi_chan@yahoo.com.
Abstract
BACKGROUND: Gigantol is a pharmacologically active bibenzyl compound exerting potential anticancer activities. At non-toxic concentrations, it reduces cancer stem cell properties and tumorigenicity. The mechanisms of the effects of gigantol on cancer cell growth are largely unknown. This study aimed to unravel the molecular profile and identify the prominent molecular mechanism of the effects of gigantol in controlling lung cancer cell proliferation. MATERIALS AND METHODS: Proteomics and bioinformatics analysis were used accompanied by experimental molecular pharmacology approaches. RESULTS: Gigantol exhibited antiproliferative effects on human lung cancer cells confirmed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide proliferation assay and colony growth assay. The protein profile in response to gigantol treatment associated with regulation of cell proliferation was analyzed to determine the prominent protein targets. Among the significant hub proteins, MYC, an important proto-oncogene and proliferation-promoting transcription factor, was down-regulated with the highest number of protein-protein interactions. MYC down-regulation was confirmed by western blot analysis. The up-stream regulator of MYC, Glycogen synthase kinase 3 beta (GSK3β) was found to be responsible for MYC destabilization mediated by gigantol. Gigantol facilitated GSK3β function and resulted in the increase of MYC-ubiquitin complex as evaluated by immunoprecipitation. CONCLUSION: Gigantol was found to inhibit lung cancer proliferation through induction of GSK3β-mediated MYC ubiquitin-proteasome degradation. These data suggest gigantol to be a promising candidate for novel strategy in inhibition of lung cancer. Copyright
BACKGROUND:Gigantol is a pharmacologically active bibenzyl compound exerting potential anticancer activities. At non-toxic concentrations, it reduces cancer stem cell properties and tumorigenicity. The mechanisms of the effects of gigantol on cancer cell growth are largely unknown. This study aimed to unravel the molecular profile and identify the prominent molecular mechanism of the effects of gigantol in controlling lung cancer cell proliferation. MATERIALS AND METHODS: Proteomics and bioinformatics analysis were used accompanied by experimental molecular pharmacology approaches. RESULTS:Gigantol exhibited antiproliferative effects on humanlung cancer cells confirmed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide proliferation assay and colony growth assay. The protein profile in response to gigantol treatment associated with regulation of cell proliferation was analyzed to determine the prominent protein targets. Among the significant hub proteins, MYC, an important proto-oncogene and proliferation-promoting transcription factor, was down-regulated with the highest number of protein-protein interactions. MYC down-regulation was confirmed by western blot analysis. The up-stream regulator of MYC, Glycogen synthase kinase 3 beta (GSK3β) was found to be responsible for MYC destabilization mediated by gigantol. Gigantol facilitated GSK3β function and resulted in the increase of MYC-ubiquitin complex as evaluated by immunoprecipitation. CONCLUSION:Gigantol was found to inhibit lung cancer proliferation through induction of GSK3β-mediated MYC ubiquitin-proteasome degradation. These data suggest gigantol to be a promising candidate for novel strategy in inhibition of lung cancer. Copyright
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