Berberine induces autophagy in glioblastoma by targeting the AMPK/mTOR/ULK1-pathway

// Jiwei Wang 1 , Qichao Qi 1 , Zichao Feng 1 , Xin Zhang 1 , Bin Huang 1 , Anjing Chen 1 , Lars Prestegarden 2, 3 , Xingang Li 1 , Jian Wang 1, 2 1 Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Jinan, 250012, P.R. China 2 Department of Biomedicine, University of Bergen, 5009 Bergen, Norway 3 Department of Dermatology, University of Bergen, 5021 Bergen, Norway Correspondence to: Xingang Li, email: lixg@sdu.edu.cn Jian Wang, email: jian.wang@uib.no Keywords : berberine, glioblastoma, autophagy, apoptosis, metabolism Received: March 15, 2016     Accepted: August 09, 2016     Published: August 19, 2016 ABSTRACT There is an urgent need for new therapeutic strategies for patients with glioblastoma multiforme (GBM). Previous studies have shown that berberine (BBR), a natural plant alkaloid, has potent anti-tumor activity. However, the mechanisms leading to cancer cell death have not been clearly elucidated. In this study, we show that BBR has profound effects on the metabolic state of GBM cells, leading to high autophagy flux and impaired glycolytic capacity. Functionally, these alterations reduce the invasive properties, proliferative potential and induce apoptotic cell death. The molecular alterations preceding these changes are characterized by inhibition of the AMPK/mTOR/ULK1 pathway. Finally, we demonstrate that BBR significantly reduces tumor growth in vivo , demonstrating the potential clinical benefits for autophagy modulating plant alkaloids in cancer therapy.