title: DNA damage dependent activation of checkpoint kinase-1 and mitogen-activated protein kinase-p38 are required in malabaricone C-induced mitochondrial cell death.
abstract: BACKGROUND
  Given that lung cancer is the second leading cause of cancer-related deaths with low survival rates, the project was aimed to formulate an efficient drug with minimum side effects, and rationalize its action mechanistically.
  
  
  METHODS
  Mitochondria deficient cells, shRNA-mediated BCL2 and ATM depleted cells and pharmacological inhibition of DNA-damage response proteins were employed to explore the signaling mechanism governed between nucleus and mitochondria in response to mal C.
  
  
  RESULTS
  Mal C decreased cell viability in three lung carcinoma cells, associated with DNA damage, p38-MAPK activation, imbalance in BAX/BCL2 expression, mitochondrial dysfunction and cytochrome-c release. Mitochondria depletion and p38-MAPK inhibition made A549 cells extremely resistant, but BCL2 knock-down partially sensitized the cells to mal C treatment. The mal C-induced apoptosis in A549 cells was initiated by DNA single strand breaks that led to double strand breaks (DSBs). DSB generation paralleled the induction of ATM- and ATR-mediated CHK1 phosphorylation. ATM silencing and ATR inhibition partially attenuated the mal C-induced p38-MAPK activation, CHK1 phosphorylation and apoptosis, which were completely suppressed by CHK1 inhibition.
  
  
  CONCLUSIONS
  Mal C activates the ATM-CHK1-p38 MAPK cascade to cause mitochondrial cell death in lung carcinoma cells.
  
  
  CONCLUSIONS
  Given that mal C has appreciable natural abundance and is non-toxic to mice, further in vivo evaluation would help in establishing its anti-cancer property.
authors.affiliation: Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400085, India.
authors.forename: Mrityunjay
authors.initials: M
authors.lastname: Tyagi
authors.affiliation: Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400085, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Bhattacharyya
authors.affiliation: Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400085, India.
authors.forename: Ajay Kumar
authors.initials: AK
authors.lastname: Bauri
authors.affiliation: Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400085, India.
authors.forename: Birija Sankar
authors.initials: BS
authors.lastname: Patro
authors.affiliation: Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400085, India. Electronic address: schatt@barc.gov.in.
authors.forename: Subrata
authors.initials: S
authors.lastname: Chattopadhyay
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000502:physiology; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004789:Enzyme Activation; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D011494:Protein Kinases / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D012118:Resorcinols / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000032:analysis; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: C494826:BAX protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D012118:Resorcinols; D051028:bcl-2-Associated X Protein; C071787:malabaricone C; D011494:Protein Kinases; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases
keywords: ATM/ATR; DNA strand break; Lung cancer cell; MAPK; Malabaricone C; Mitochondrial dysfunction