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Title: ABT737 enhances cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics

Cholangiocarcinoma responses weakly to cisplatin. Mitochondrial dynamics participate in the response to various stresses, and mainly involve mitophagy and mitochondrial fusion and fission. Bcl-2 family proteins play critical roles in orchestrating mitochondrial dynamics, and are involved in the resistance to cisplatin. Here we reported that ABT737, combined with cisplatin, can promote cholangiocarcinoma cells to undergo apoptosis. We found that the combined treatment decreased the Mcl-1 pro-survival form and increased Bak. Cells undergoing cisplatin treatment showed hyperfused mitochondria, whereas fragmentation was dominant in the mitochondria of cells exposed to the combined treatment, with higher Fis1 levels, decreased Mfn2 and OPA1 levels, increased ratio of Drp1 60 kD to 80 kD form, and more Drp1 located on mitochondria. More p62 aggregates were observed in cells with fragmented mitochondria, and they gradually translocated to mitochondria. Mitophagy was induced by the combined treatment. Knockdown p62 decreased the Drp1 ratio, increased Tom20, and increased cell viability. Our data indicated that mitochondrial dynamics play an important role in the response of cholangiocarcinoma to cisplatin. ABT737 might enhance cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics and the balance within Bcl-2 family proteins. Furthermore, p62 seems to be critical in the regulation of mitochondrial dynamics. -more » Highlights: • Cholangiocarcinoma may adapt to cisplatin through mitochondrial fusion. • ABT737 sensitizes cholangiocarcinoma to cisplatin by promoting fission and mitophagy. • p62 might participate in the regulation of mitochondrial fission and mitophagy.« less
Authors:
 [1] ;  [2] ;  [3] ; ; ;  [4] ;  [2] ;  [2] ;  [1]
  1. Department of Hepatobiliary & Pancreas Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021 (China)
  2. Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021 (China)
  3. Bethune Medical College, Jilin University, Changchun, Jilin 130021 (China)
  4. State Key Laboratory of Luminescence and Applications, Changchun Institute of Optics, Fine Mechanics and Physics, Chinese Academy of Sciences, Changchun, Jilin 130033 (China)
Publication Date:
OSTI Identifier:
22462301
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 335; Journal Issue: 1; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACETATES; APOPTOSIS; ATROPHY; BORON CHLORIDES; BROMIDES; DEATH; FRAGMENTATION; LEUKEMIA; LYMPHOMAS; MEMBRANES; MICROTUBULES; MITOCHONDRIA; MORPHOLOGY; OXYGEN; PERMEABILITY; PHOSPHATES; POTENTIALS; PROMOTERS; PROTEINS; SENSITIVITY; SIGNALS; STRESSES; VIABILITY