Cisplatin Resistance Associated with PARP Hyperactivation
2013 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 7, 2271-2280 p.Article in journal (Refereed) Published
Non-small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR(high)) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor-induced apoptosis. Cancer Res; 73(7); 2271-80.
Place, publisher, year, edition, pages
Philadelphia: American Association for Cancer Research , 2013. Vol. 73, no 7, 2271-2280 p.
Cancer and Oncology
IdentifiersURN: urn:nbn:se:umu:diva-70139DOI: 10.1158/0008-5472.CAN-12-3000ISI: 000316995600024OAI: oai:DiVA.org:umu-70139DiVA: diva2:620628