Carcinogenesis Advance Access originally published online on April 15, 2008
Carcinogenesis 2008 29(6):1124-1133; doi:10.1093/carcin/bgn093
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Bioenergetic differences selectively sensitize tumorigenic liver progenitor cells to a new gold(I) compound
1 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
2 Biochemistry, School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia
3 Department of Biochemistry, La Trobe University, Victoria 3086, Australia
4 Chemistry, School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia
5 Australian Research Council Centre of Excellence in Plant Energy Biology, The University of Western Australia, Western Australia 6009, Australia
* To whom correspondence should be addressed. Tel: +61 8 9224 0330; Fax: +61 8 9224 0322; Email: afilipov{at}waimr.uwa.edu.au
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 (
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 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 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.
Abbreviations: ATP, adenosine triphosphate; BMOL, bipotential murine oval liver; cIAP, cellular inhibitor of apoptosis protein; DHE, dihydroethidium; DLC, delocalized lipophilic cation; HCC, hepatocellular carcinoma; [(iPr2Im)2Au]Cl, bis(1,3-di-isopropylimidazol-2-ylidene)gold(I) chloride; (iPr2Im)AuCl, 1,3-di-isopropylimidazol-2-ylidenegold(I) chloride; LPC, liver progenitor cell; MnSOD, manganese superoxide disumutase; m, mitochondrial membrane potential; PIL, p53-immortalized liver; ROS, reactive oxygen species; TPMP, methyltriphenylphosphonium; Yap, yes-associated protein
Received February 20, 2008; revised March 20, 2008; accepted March 26, 2008.