Gigantol Targets MYC for Ubiquitin-proteasomal Degradation and Suppresses Lung Cancer Cell Growth

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, 5dimethylthiazol-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 proliferationpromoting transcription factor, was down-regulated with the highest number of protein-protein interactions. MYC downregulation was confirmed by western blot analysis. The upstream 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. Evading growth suppression and sustaining proliferation are among the hallmarks of cancer and lead to disease progression (1). Cell proliferation is an increase in the number of cells as a result of cell growth and cell division, and rapid proliferation is considered an aggressive factor of cancer and is correlated with poor prognosis (2, 3). Dysregulation of proliferation signals and oncogenes is known to drive carcinogenesis and tumor growth (4, 5). There are several oncogenes that control cancer cell growth. MYC, a proto-oncogene, is a central transcription factor that controls cell proliferation, differentiation, and apoptosis. Amplification or overexpression of MYC occurs in various cancer types, including lung cancer, and was shown to be related to poor survival (6). An inhibition of MYC may offer an effective therapeutic treatment via tumor growth suppression (7, 8). However, as targeted therapy against MYC is still elusive due to its lack of inhibitory binding site, modulation of the MYC level via targeting its upstream regulators is a potential strategy (6). Glycogen synthase kinase 3 beta (GSK3β) showed prominent tumorsuppressor properties in lung cancer (9). Protein kinase B (AKT1)-dependent GSK3β phosphorylation at Ser9 was shown to be correlated with poor survival rate of patients with lung cancer (10). GSK3β s...

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