Kavalactone yangonin induces autophagy and sensitizes bladder cancer cells to flavokawain A and docetaxel via inhibition of the mTOR pathway

Consumption of kava （Piper methysticum Forst） has been linked to reduced cancer risk in the South Pacific Islands.Kavalactones are major bioactive components in kava root extracts, which have recently demonstrated anti-canceractivities. However, molecular mechanisms of kavalactones＇ anti-cancer action remain largely unknown. We haveidentified two kavalactones, yangonin and 5＇ 6＇-dehydrokawain, as potent inducers ofautophagic cell death in bladdercancer cells. The effect of yangonin inducing autophagy is associated with increased expression ofbeclin and ATG5.In addition, yangonin increases the expression of LKB 1 and decreases the phosphorylation of Akt, PRAS40, rpS6,p70S6K and 4E-BP1, leading to increased binding of 4E-BP1 to m7 GTP. The growth inhibitory effects ofyangoninwere attenuated in TSC1 or LKB1 knockout mouse embryonic fibroblasts, suggesting that TSC1 and LKB1expression may contribute to optimal growth inhibition by yangonin. Furthermore, yangonin reduces the viability ofbladder cancer cell lines derived from different stages of human bladder cancer, and acts synergistically withapoptosis-inducing agents such as docetaxel and flavokawain A. Our results support a novel anti-bladder cancermechanism by yangonin and further studies are needed to assess the potential use of yangonin for bladder cancerprevention and treatment.