title: Guttiferone K induces autophagy and sensitizes cancer cells to nutrient stress-induced cell death.
abstract: BACKGROUND
  Medicinal plants have long been an excellent source of pharmaceutical agents. Autophagy, a catabolic degradation process through lysosomes, plays an important role in tumorigenesis and cancer therapy.
  
  
  OBJECTIVE
  Through a screen designed to identify autophagic regulators from a library of natural compounds, we found that Guttiferone K (GUTK) can activate autophagy in several cancer cell lines. The objective of this study is to investigate the mechanism by which GUTK sensitizes cancer cells to cell death in nutrient starvation condition.
  
  
  METHODS
  Cell death analysis was performed by propidium iodide staining with flow cytometry or Annexin V-FITC/PI staining assay. DCFH-DA staining was used for intracellular ROS measurement. Protein levels were analyzed by western blot analysis. Cell viability was measured by MTT assay.
  
  
  RESULTS
  Exposure to GUTK was observed to markedly induce GFP-LC3 puncta formation and activate the accumulation of LC3-II and the degradation of p62 in HeLa cells, suggesting that GUTK is an autophagy inducer. Importantly, hydroxychloroquine, an autophagy inhibitor, was found to significantly prevent GUTK-induced cell death in nutrient starvation conditions, suggesting that the cell death observed is largely dependent on autophagy. We further provide evidence that GUTK inhibits Akt phosphorylation, thereby inhibiting the mTOR pathway in cancer cells during nutrient starvation. In addition, GUTK causes the accumulation of reactive oxygen species (ROS) and the phosphorylation of JNK in EBSS, which may mediate both autophagy and apoptosis.
  
  
  CONCLUSIONS
  These data indicate that GUTK sensitizes cancer cells to nutrient stress-induced cell death though Akt/mTOR dependent autophagy pathway.
authors: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, P.R. China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, P.R. China.
authors: Man
authors: M
authors: Wu
authors: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, P.R. China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, P.R. China.
authors: Yuanzhi
authors: Y
authors: Lao
authors: Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, P.R. China.
authors: Naihan
authors: N
authors: Xu
authors: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, P.R. China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, P.R. China.
authors: Xiaoyu
authors: X
authors: Wang
authors: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, P.R. China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, P.R. China.
authors: Hongsheng
authors: H
authors: Tan
authors: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, P.R. China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, P.R. China.
authors: Wenwei
authors: W
authors: Fu
authors: Faculty of Science, School of Chinese Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors: Zhixiu
authors: Z
authors: Lin
authors: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, P.R. China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, P.R. China. Electronic address: xuhongxi88@gmail.com.
authors: Hongxi
authors: H
authors: Xu
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001343:Autophagy; D001577:Benzophenones / Q000494:pharmacology*; D016923:Cell Death; D045744:Cell Line, Tumor; D003470:Culture Media / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001577:Benzophenones; D003470:Culture Media; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C118585:P62 protein, human; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; C519762:guttiferone K; D006886:Hydroxychloroquine; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Apoptosis; Autophagy; Guttiferone K; Natural compound; Starvation