Bioenergetic differences selectively sensitize tumorigenic liver progenitor cells to a new gold(I) compound

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Title Bioenergetic differences selectively sensitize tumorigenic liver progenitor cells to a new gold(I) compound
Author Jellicoe, Matthew M.; Nichols, Scott J.; Callus, Bernard A.; Baker, Murray V.; Barnard, Peter J.; Berners-Price, Sue; Whelan, James; Yeoh, George C.; Filipovska, Aleksandra
Journal Name Carcinogenesis
Year Published 2008
Place of publication United Kingdom
Publisher Oxford University Press
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 (Δψm) 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 Δψm 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 Δψm, 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.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1093/carcin/bgn093
Volume 29
Issue Number 6
Page from 1124
Page to 1133
ISSN 0143-3334
Date Accessioned 2011-07-15
Date Available 2011-08-12T06:22:22Z
Language en_AU
Research Centre Institute for Glycomics
Faculty Faculty of Science, Environment, Engineering and Technology
Subject Inorganic Chemistry
URI http://hdl.handle.net/10072/39998
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1x

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