Carcinogenesis Advance Access published online on April 15, 2008
Carcinogenesis, doi:10.1093/carcin/bgn093
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, University of Western Australia, Western Australia 6009, Australia
Request for reprints and to whom correspondence should be addressed: Dr. Aleksandra Filipovska, Western Australian Institute for Medical Research, Level 6, Medical Research Foundation Building, Rear 50 Murray Street, Perth, Western Australia 6000, Australia. Fax: +61 8 9224 0322; E-mail: afilipov{at}waimr.uwa.edu.au. This work was supported in part by grants from the National Health and Medical Research Council, the Cancer Council of WA and the Australian Research Council.
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 lines (LPC), one non-tumorigenic (PIL4) the other tumorigenic (PIL2). Analysis of these cell lines and a p53 wild type non-tumorigenic cell line (BMOL) revealed an increase in expression of genes encoding the antiapoptotic proteins cIAP1 and Yap in the PIL2 cells which resulted in an increase in the protein encoded by these genes. PIL2 cells have higher mitochondrial membrane potential (
øm) compared to PIL4 and BMOL and had greater levels of reactive oxygen species, despite the fact that the mitochondrial antioxidant enzyme, manganese superoxide dismutase, was elevated at transcript and protein levels. Taken together these results may account for the observed resistance of PIL2 cells to apoptotic stimuli compared to PIL4. We tested a new gold compound to show that hyperpolarized øm led to its increased accumulation in mitochondria of PIL2 cells. This compound selectively induces apoptosis in PIL2 cells but not in PIL4 nor BMOL. The gold compound depolarized the øm, depleted the ATP pool and activated caspase-3 and caspase-9, suggesting apoptosis was mediated via mitochondria. This investigation shows that the non-tumorigenic and tumorigenic LPC 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.
Key Words: liver progenitor cells • antitumor agents • mitochondria • gold compounds • apoptosis
Received February 20, 2008; revised March 20, 2008; accepted March 26, 2008.