Kava and DHM inhibit chronic hexavalent chromium exposure-induced cell malignant transformation through down-regulating RNA splicing factor SNRPA1 expression

Hexavalent chromium [Cr(VI)] is a common occupational and environmental toxicant and an established carcinogen causing lung cancer in humans. The mechanism through which Cr(VI) exposure causes lung cancer remains to be clearly defined. No effective strategies are currently available to prevent lung cancer resulting from chronic Cr(VI) exposure. Kava is traditionally consumed by south Pacific islanders to reduce anxiety. Epidemiology and experimental studies suggest that Kava has anticancer potential and may be used as a preventive agent to reduce the risk of various cancers including lung cancer. The purpose of this study is to determine the effect of Kava and its active component dihydromethysticin (DHM) on chronic Cr(VI) exposure-induced cell malignant transformation and the underlying mechanism. The study was performed by pre-treating immortalized but non-tumorigenic human bronchial epithelial cells (BEAS-2B) with Kava (25 µg/ml) or DHM (10 µM) followed by exposing cells to 0.25 µM of Cr(VI) (K2Cr2O7) for 20 weeks to determine the impact of Kava or DHM on chronic Cr(VI) exposure-induced cell transformation, cancer stem cell (CSC)-like property and tumorigenesis. The extent of cell transformation was evaluated by soft agar colony formation assay, Western blot analysis of cancer stemness marker expression levels and nude mouse xenograft tumorigenesis assay. It was found that Kava or DHM pre-treatment significantly reduces Cr(VI)-induced cell transformation, CSC-like property and tumorigenesis. Mechanistically, it was determined that Kava or DHM impairs Cr(VI)-induced cell transformation by down-regulating RNA splicing factor small nuclear ribonucleoprotein polypeptide A' (SNRPA1) expression to reduce the protooncogene, cancer stemness marker and driver c-MYC expression. It was further determined that DHM/SNRPA1 regulate c-MYC expression through affecting c-MYC protein stability. It was concluded that Kava or DHM inhibits Cr(VI)-induced cell transformation, CSC-like property and tumorigenesis by down-regulating RNA splicing factor SNRPA1 expression to increase the protooncogene c-MYC protein degradation.