Mitochondria-derived reactive oxygen species drive GANT61-induced mesothelioma cell apoptosis

Chuan Bian Lim, Cecilia M. Prêle, Svetlana Baltic, Peter G. Arthur, Jenette Creaney, D. Neil Watkins, Philip J. Thompson, Steven E. Mutsaers

Research output: Contribution to journalArticleResearchpeer-review

26 Citations (Scopus)

Abstract

Gli transcription factors of the Hedgehog (Hh) pathway have been reported to be drivers of malignant mesothelioma (MMe) cell survival. The Gli inhibitor GANT61 induces apoptosis in various cancer cell models, and has been associated directly with Gli inhibition. However various chemotherapeutics can induce cell death through generation of reactive oxygen species (ROS) but whether ROS mediates GANT61-induced apoptosis is unknown. In this study human MMe cells were treated with GANT61 and the mechanisms regulating cell death investigated. Exposure of MMe cells to GANT61 led to G1 phase arrest and apoptosis, which involved ROS but not its purported targets, GLI1 or GLI2. GANT61 triggered ROS generation and quenching of ROS protected MMe cells from GANT61-induced apoptosis. Furthermore, we demonstrated that mitochondria are important in mediating GANT61 effects: (1) ROS production and apoptosis were blocked by mitochondrial inhibitor rotenone; (2) GANT61 promoted superoxide formation in mitochondria; and (3) mitochondrial DNA-deficient LO68 cells failed to induce superoxide, and were more resistant to apoptosis induced by GANT61 than wild-type cells. Our data demonstrate for the first time that GANT61 induces apoptosis by promoting mitochondrial superoxide generation independent of Gli inhibition, and highlights the therapeutic potential of mitochondrial ROS-mediated anticancer drugs in MMe.

Original languageEnglish
Pages (from-to)1519-1530
Number of pages12
JournalOncotarget
Volume6
Issue number3
DOIs
Publication statusPublished - 2015
Externally publishedYes

Keywords

  • Apoptosis
  • GANT61
  • Hedgehog
  • Mesothelioma
  • Reactive oxygen species

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