title: Mitochondrial ATF2 translocation contributes to apoptosis induction and BRAF inhibitor resistance in melanoma through the interaction of Bim with VDAC1.
abstract: BACKGROUND
  The mitochondrial accumulation of ATF2 is involved in tumor suppressor activities via cytochrome c release in melanoma cells. However, the signaling pathways that connect mitochondrial ATF2 accumulation and cytochrome c release are not well documented.
  
  
  METHODS
  Several melanoma cell lines, B16F10, K1735M2, A375 and A375-R1, were treated with paclitaxel and vemurafenib to test the function of mitochondrial ATF2 and its connection to Bim and voltage-dependent anion channel 1 (VDAC1). Immunoprecipitation analysis was performed to investigate the functional interaction between the involved proteins. VDAC1 oligomerization was evaluated using an EGS-based crosslinking assay.
  
  
  RESULTS
  The expression and migration of ATF2 to the mitochondria accounted for paclitaxel stimuli and acquired resistance to BRAF inhibitors. Mitochondrial ATF2 facilitated Bim stabilization through the inhibition of its degradation by the proteasome, thereby promoting cytochrome c release and inducing apoptosis in B16F10 and A375 cells. Studies using B16F10 and A375 cells genetically modified for ATF2 indicated that mitochondrial ATF2 was able to dissociate Bim from the Mcl-1/Bim complex to trigger VDAC1 oligomerization. Immunoprecipitation analysis revealed that Bim interacts with VDAC1, and this interaction was remarkably enhanced during apoptosis.
  
  
  CONCLUSIONS
  These results reveal that mitochondrial ATF2 is associated with the induction of apoptosis and BRAF inhibitor resistance through Bim activation, which might suggest potential novel therapies for the targeted induction of apoptosis in melanoma therapy.
authors.affiliation: Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, P. R. China.|Department of Pathology, Linyi People's Hospital, Linyi, Shandong, P. R. China.
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, P. R. China.|Department of Pathology, Linyi People's Hospital, Linyi, Shandong, P. R. China.
authors.forename: Qingjuan
authors.initials: Q
authors.lastname: Shang
authors.affiliation: Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, P. R. China.
authors.forename: Zhaoyun
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, P. R. China.|Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, P. R. China.
authors.forename: Chun
authors.initials: C
authors.lastname: Deng
authors.affiliation: Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, P. R. China.
authors.forename: Chunbao
authors.initials: C
authors.lastname: Guo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D014162:Transfection; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C494762:VDAC1 protein, human; D050995:Voltage-Dependent Anion Channel 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: ATF2; Bim; Mcl-1; VDAC1; mitochondria