ABT737 enhances cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics

Exp Cell Res. 2015 Jul 1;335(1):68-81. doi: 10.1016/j.yexcr.2015.04.016. Epub 2015 Apr 30.

Abstract

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 60kD to 80kD 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.

Keywords: Bcl-2 family; Cholangiocarcinoma; Cisplatin; Mitochondrial morphology; Mitophagy; p62.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Apoptosis / drug effects
  • Bile Duct Neoplasms / drug therapy*
  • Bile Ducts, Intrahepatic*
  • Biphenyl Compounds / administration & dosage*
  • Cell Line
  • Cell Survival / drug effects
  • Cholangiocarcinoma / drug therapy*
  • Cisplatin / administration & dosage*
  • Drug Resistance, Neoplasm / drug effects*
  • Dynamins
  • GTP Phosphohydrolases / metabolism
  • Humans
  • Membrane Proteins / metabolism
  • Membrane Transport Proteins / metabolism
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitochondrial Dynamics / drug effects
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Mitochondrial Proteins / metabolism
  • Mitophagy / drug effects
  • Myeloid Cell Leukemia Sequence 1 Protein / biosynthesis
  • Nitrophenols / administration & dosage*
  • Piperazines / administration & dosage
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • RNA Interference
  • RNA, Small Interfering / genetics
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Receptors, Cell Surface / metabolism
  • Sulfonamides / administration & dosage*
  • bcl-2 Homologous Antagonist-Killer Protein / biosynthesis

Substances

  • ABT-737
  • BAK1 protein, human
  • Biphenyl Compounds
  • FIS1 protein, human
  • MCL1 protein, human
  • Membrane Proteins
  • Membrane Transport Proteins
  • Microtubule-Associated Proteins
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Mitochondrial Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nitrophenols
  • P62 protein, human
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Receptors, Cell Surface
  • Sulfonamides
  • TOMM20 protein, human
  • bcl-2 Homologous Antagonist-Killer Protein
  • GTP Phosphohydrolases
  • MFN2 protein, human
  • OPA1 protein, human
  • DNM1L protein, human
  • Dynamins
  • Cisplatin