title: bis-Dehydroxy-Curcumin triggers mitochondrial-associated cell death in human colon cancer cells through ER-stress induced autophagy.
abstract: BACKGROUND
  The activation of autophagy has been extensively described as a pro-survival strategy, which helps to keep cells alive following deprivation of nutrients/growth factors and other stressful cellular conditions. In addition to cytoprotective effects, autophagy can accompany cell death. Autophagic vacuoles can be observed before or during cell death, but the role of autophagy in the death process is still controversial. A complex interplay between autophagy and apoptosis has come to light, taking into account that numerous genes, such as p53 and Bcl-2 family members, are shared between these two pathways.
  
  
  RESULTS
  In this study we showed a potent and irreversible cytotoxic activity of the stable Curcumin derivative bis-DeHydroxyCurcumin (bDHC) on human colon cancer cells, but not on human normal cells. Autophagy is elicited by bDHC before cell death as demonstrated by increased autophagosome formation -measured by electron microscopy, fluorescent LC3 puncta and LC3 lipidation- and autophagic flux -measured by interfering LC3-II turnover. The accumulation of poly-ubiquitinated proteins and ER-stress occurred upstream of autophagy induction and resulted in cell death. Cell cycle and Western blot analyses highlighted the activation of a mitochondrial-dependent apoptosis, which involves caspase 7, 8, 9 and Cytochrome C release. Using pharmacological inhibitions and RNAi experiments, we showed that ER-stress induced autophagy has a major role in triggering bDHC-cell death.
  
  
  CONCLUSIONS
  Our findings describe the mechanism through which bDHC promotes tumor selective inhibition of proliferation, providing unequivocal evidence of the role of autophagy in contrasting the proliferation of colon cancer cells.
authors: Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, via Campi 213/D, Modena, Italy.
authors: Valentina
authors: V
authors: Basile
authors: Silvia
authors: S
authors: Belluti
authors: Erika
authors: E
authors: Ferrari
authors: Chiara
authors: C
authors: Gozzoli
authors: Sonia
authors: S
authors: Ganassi
authors: Daniela
authors: D
authors: Quaglino
authors: Monica
authors: M
authors: Saladini
authors: Carol
authors: C
authors: Imbriano
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D036381:Diarylheptanoids; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D036381:Diarylheptanoids; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C581965:bis-dehydroxy-curcumin; D020169:Caspases; D003474:Curcumin