title: Bioenergetic differences selectively sensitize tumorigenic liver progenitor cells to a new gold(I) compound.
abstract: A hallmark of cancer cells is their ability to evade apoptosis and mitochondria play a critical role in this process. Delineating mitochondrial differences between normal and cancer cells has proven challenging due to the lack of matched cell lines. Here, we compare two matched liver progenitor cell (LPC) lines, one non-tumorigenic [p53-immortalized liver (PIL) 4] and the other tumorigenic (PIL2). Analysis of these cell lines and a p53 wild-type non-tumorigenic cell line [bipotential murine oval liver (BMOL)] revealed an increase in expression of genes encoding the antiapoptotic proteins cellular inhibitor of apoptosis protein (cIAP) 1 and yes associate protein in the PIL2 cells, which resulted in an increase in the protein encoded by these genes. PIL2 cells have higher mitochondrial membrane potential (Deltapsi(m)) compared with PIL4 and BMOL and had greater levels of reactive oxygen species, despite the fact that the mitochondrial antioxidant enzyme, manganese superoxide disumutase, was elevated at transcript and protein levels. Taken together, these results may account for the observed resistance of PIL2 cells to apoptotic stimuli compared with PIL4. We tested a new gold compound to show that hyperpolarized Deltapsi(m) led to its increased accumulation in mitochondria of PIL2 cells. This compound selectively induces apoptosis in PIL2 cells but not in PIL4 or BMOL. The gold compound depolarized the Deltapsi(m), depleted the adenosine triphosphate pool and activated caspase-3 and caspase-9, suggesting that apoptosis was mediated via mitochondria. This investigation shows that the non-tumorigenic and tumorigenic LPCs are useful models to delineate the role of mitochondrial dysfunction in tumorigenesis and for the future development of mitochondria-targeted chemotherapeutics that selectively target tumor cells.
authors.affiliation: Laboratory for Cancer Medicine, Western Australian Institute for Medical Research and Center for Medical Research, The University of Western Australia, Perth, Western Australia 6000, Australia.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Jellicoe
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Nichols
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Callus
authors.forename: Murray V
authors.initials: MV
authors.lastname: Baker
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnard
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Berners-Price
authors.forename: James
authors.initials: J
authors.lastname: Whelan
authors.forename: George C
authors.initials: GC
authors.lastname: Yeoh
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Filipovska
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004734:Energy Metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D017612:Gold Compounds / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D015151:Immunoblotting; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D046228:Microarray Analysis; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D017612:Gold Compounds; D051034:Inhibitor of Apoptosis Proteins; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse