Involvement of both intrinsic and extrinsic pathways in IFN-gamma-induced apoptosis that are enhanced with cisplatin.
IFN-gamma has direct anti-proliferative effects on ovarian cancer cell lines and tumour cells isolated from ovarian cancer ascites. The aim of this study was to further elucidate the mechanisms involved. An IFN-gamma-mediated cell cycle blockade was detectable in synchronised cell populations. Apoptosis, which was caspase dependent, was also induced. When caspase activity was blocked, the anti-proliferative effect of IFN-gamma was only partially reduced indicating independent roles for both growth inhibition and apoptosis in its actions. We have demonstrated involvement of the intrinsic apoptotic pathway; IFN-gamma treatment resulted in mitochondrial membrane depolarisation, cytochrome c release into the cytosol and activation of caspase 9. Cytochrome c release was blocked by the presence of a general caspase inhibitor, suggesting a role for caspases upstream of the mitochondria. One candidate is caspase 8, which was also activated in cells treated with IFN-gamma. Levels of Bid, a pro-apoptotic molecule that can mediate mitochondrial membrane permeabilisation when cleaved by caspase 8, were also decreased and indicated a potential link between these two pathways in IFN-gamma-induced apoptosis. Furthermore, together with cisplatin, IFN-gamma exerted a more powerful anti-proliferative effect.
Barton
Caroline
C
Cancer Research UK Translational Oncology Laboratory, Barts and the London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square.
Davies
Derek
D
Balkwill
Fran
F
Burke
Frances
F
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects; D011994:Recombinant Proteins
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D011994:Recombinant Proteins; D007371:Interferon-gamma; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin