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

Oncogene (2016) 35, 427437 2016 Macmillan Publishers Limited All rights reserved 0950-9232/16

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ORIGINAL ARTICLE

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

L Potze1, S Di Franco1,2, C Grandela1, ML Pras-Raves3, DI Picavet4, HA van Veen4, H van Lenthe5, FB Mullauer1, NN van der Wel4, A Luyf3, AHC van Kampen3, S Kemp5, V Everts4, JH Kessler1, FM Vaz5 and JP Medema1

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-dened 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 nd that inhibition of SCD-1 by BetA or, alternatively, with a specic 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.

Oncogene (2016) 35, 427437; doi:http://dx.doi.org/10.1038/onc.2015.102

Web End =10.1038/onc.2015.102 ; published online 20 April 2015

INTRODUCTIONCancer is characterized by cell growth and proliferation, which requires an enormous surge in novel building blocks, such as nucleic acids, lipids and amino acids. To meet these requirements, cancer cells undergo major changes in their metabolism. For instance, lipid metabolism undergoes a dramatic shift towards lipid synthesis.13 For cellular lipid production, fatty acids (FAs) are needed as building...