1. Academic Validation
  2. Betulinic acid induces a novel cell death pathway that depends on cardiolipin modification

Betulinic acid induces a novel cell death pathway that depends on cardiolipin modification

  • Oncogene. 2016 Jan 28;35(4):427-37. doi: 10.1038/onc.2015.102.
L Potze 1 S Di Franco 1 2 C Grandela 1 M L Pras-Raves 3 D I Picavet 4 H A van Veen 4 H van Lenthe 5 F B Mullauer 1 N N van der Wel 4 A Luyf 3 A H C van Kampen 3 S Kemp 5 V Everts 4 J H Kessler 1 F M Vaz 5 J P Medema 1
Affiliations

Affiliations

  • 1 Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
  • 2 Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy.
  • 3 Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Bioinformatics Laboratory, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
  • 4 Department of Cell Biology and Histology, Core facility Cellular Imaging University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
  • 5 Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
Abstract

Cancer is associated with strong changes in lipid metabolism. For instance, normal cells take up fatty acids (FAs) from the circulation, while tumour cells generate their own and become dependent on de novo FA synthesis, which could provide a vulnerability to target tumour cells. Betulinic acid (BetA) is a natural compound that selectively kills tumour cells through an ill-defined mechanism that is independent of Bax and Bak, but depends on mitochondrial permeability transition-pore opening. Here we unravel this pathway and show that BetA inhibits the activity of steroyl-CoA-desaturase (SCD-1). This Enzyme is overexpressed in tumour cells and critically important for cells that utilize de novo FA synthesis as it converts newly synthesized saturated FAs to unsaturated FAs. Intriguingly, we find that inhibition of SCD-1 by BetA or, alternatively, with a specific SCD-1 inhibitor directly and rapidly impacts on the saturation level of cardiolipin (CL), a mitochondrial lipid that has important structural and metabolic functions and at the same time regulates mitochondria-dependent cell death. As a result of the enhanced CL saturation mitochondria of Cancer cells, but not normal cells that do not depend on de novo FA synthesis, undergo ultrastructural changes, release cytochrome c and quickly induce cell death. Importantly, addition of unsaturated FAs circumvented the need for SCD-1 activity and thereby prevented BetA-induced CL saturation and subsequent cytotoxicity, supporting the importance of this novel pathway in the cytotoxicity induced by BetA.

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