title: Betulinic acid induces a novel cell death pathway that depends on cardiolipin modification.
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.
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Potze
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.|Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Di Franco
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Grandela
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Bioinformatics Laboratory, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: M L
authors.initials: ML
authors.lastname: Pras-Raves
authors.affiliation: Department of Cell Biology and Histology, Core facility Cellular Imaging University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: D I
authors.initials: DI
authors.lastname: Picavet
authors.affiliation: Department of Cell Biology and Histology, Core facility Cellular Imaging University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: H A
authors.initials: HA
authors.lastname: van Veen
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: van Lenthe
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: F B
authors.initials: FB
authors.lastname: Mullauer
authors.affiliation: Department of Cell Biology and Histology, Core facility Cellular Imaging University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: N N
authors.initials: NN
authors.lastname: van der Wel
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Bioinformatics Laboratory, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Luyf
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Bioinformatics Laboratory, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: A H C
authors.initials: AH
authors.lastname: van Kampen
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Kemp
authors.affiliation: Department of Cell Biology and Histology, Core facility Cellular Imaging University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: V
authors.initials: V
authors.lastname: Everts
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Kessler
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: F M
authors.initials: FM
authors.lastname: Vaz
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: J P
authors.initials: JP
authors.lastname: Medema
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002308:Cardiolipins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053978:Pentacyclic Triterpenes; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002308:Cardiolipins; D005227:Fatty Acids; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D045304:Cytochromes c; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase; D000094062:Betulinic Acid