Involvement of E-cadherin/AMPK/mTOR axis in LKB1-induced sensitivity of non-small cell lung cancer to gambogic acid.

Liver kinase B1 (LKB1) is a tumor suppressor that functions as master regulator of cell growth, metabolism, survival, and polarity. Patients with NSCLC possessing mutated LKB1 respond to chemotherapy differently from those with wild-type LKB1. Gambogic acid (GA), a small molecule from natural product, has been established as an anti-tumor agent due to its potent activity and low toxicity. Here, we find out that NSCLC cells with wild-type LKB1 are more sensitive to GA in vitro and in vivo. Mechanistic studies pinpoint that the selective inhibition of mTOR signaling confers the stronger suppression of NSCLC in presence of wild-type LKB1, which is involved in the enhancement of p-AMPK. Further studies reveal that GA increases p-AMPK levels through up-regulation of E-cadherin associated with LKB1. In addition, induction of E-cadherin by GA may be through down-regulation of ZEB1, which is independent with LKB1 status. Hence, our findings support that enhanced E-cadherin by GA cooperates LKB1, leading to up-regulation of p-AMPK, and thus blocking of mTOR signaling pathway, which provide theoretical foundation for utilization of GA as a potential targeted drug against NSCLC harboring wild-type LKB1.