The Mechanism Of Honokiol Induced Cancer Cell Apoptosis Via Antagonizing TNFα Induced Nur77/LKB1Suvival Signaling Pathway

Both historically and contemporarily, cancer is seen as an inflammatory process. Evidence has emerged in the last two decades that at the molecular level most chronic diseases, including cancer, are caused by dysregulated inflammatory response. TNFa, a major inflammatory cytokine with various biological activities such as maintenance and homeostasis of host defence and the immune system, has now been shown to involve in malignant disease and pathological injury when it is excessive. This paper supports a possible new mechanism through which TNFa may promote cancer progression via suppressing LKB1-AMPK signaling pathway by Nur77, and the work also explains the proapoptotic function of Honokiol through promoting Nur77degradation.Liver kinase B1(LKB1), known as a tumor suppressor, has important roles in governing energy homeostasis by regulating the activity of the energy sensor kinase AMP-activated protein kinase (AMPK). Activation of AMPK by LKB1suppresses growth and proliferation The orphan nuclear receptor Nur77binds and sequesters LKB1in the nucleus, thereby attenuating AMPK activation We are the first to find that TNFa could inhibit LKB1-AMPK axis by enhancing Nur77-LKB1direct interaction, thus promoting tumorigenesis. Apart from that, we also discovered that Honokiol antagonized TNFa and induced cancer cell apoptosis. The potent mechanism is that the pro-degradation function of Honokiol to Nur77released LKB1and had it translocate from nucleus to cytoplasm which was followed by activating AMPK and inducing cancer cell apoptosis.With the emergence of the inflammatory tumor microenvironment as an essential ingredient of cancer malignancy, therapies targeting the host compartment of tumors have begun to be designed and applied in the clinic. Honokiol, as a TNFa antagonist and a potential antitumor drug, presents a new hope for future cancer treatment.