Reduced proficiency in Homologous Recombination underlies the high sensitivity of embryonal carcinoma Testicular Germ Cell Tumors to cisplatin and poly (ADP-ribose) polymerase inhibition Journal Article

   

Authors:	Cavallo, F.; Graziani, G.; Antinozzi, C.; Feldman, D. R.; Houldsworth, J.; Bosl, G. J.; Chaganti, R. S. K.; Moynahan, M. E.; Jasin, M.; Barchi, M.
Article Title:	Reduced proficiency in Homologous Recombination underlies the high sensitivity of embryonal carcinoma Testicular Germ Cell Tumors to cisplatin and poly (ADP-ribose) polymerase inhibition
Abstract:	Testicular Germ Cell Tumors (TGCT) and patient-derived cell lines are extremely sensitive to cisplatin and other interstrand cross-link (ICL) inducing agents. Nevertheless, a subset of TGCTs are either innately resistant or acquire resistance to cisplatin during treatment. Understanding the mechanisms underlying TGCT sensitivity/resistance to cisplatin as well as the identification of novel strategies to target cisplatin-resistant TGCTs have major clinical implications. Herein, we have examined the proficiency of five embryonal carcinoma (EC) cell lines to repair cisplatin-induced ICLs. Using γH2AX staining as a marker of double strand break formation, we found that EC cell lines were either incapable of or had a reduced ability to repair ICL-induced damage. The defect correlated with reduced Homologous Recombination (HR) repair, as demonstrated by the reduction of RAD51 foci formation and by direct evaluation of HR efficiency using a GFP-reporter substrate. HR-defective tumors cells are known to be sensitive to the treatment with poly(ADP-ribose) polymerase (PARP) inhibitor. In line with this observation, we found that EC cell lines were also sensitive to PARP inhibitor monotherapy. The magnitude of sensitivity correlated with HR-repair reduced proficiency and with the expression levels and activity of PARP1 protein. In addition, we found that PARP inhibition strongly enhanced the response of the most resistant EC cells to cisplatin, by reducing their ability to overcome the damage. These results point to a reduced proficiency of HR repair as a source of sensitivity of ECs to ICL-inducing agents and PARP inhibitor monotherapy, and suggest that pharmacological inhibition of PARP can be exploited to target the stem cell component of the TGCTs (namely ECs) and to enhance the sensitivity of cisplatin-resistant TGCTs to standard treatments. © 2012 Cavallo et al.
Journal Title:	PLoS ONE
Volume:	7
Issue:	12
ISSN:	1932-6203
Publisher:	Public Library of Science
Date Published:	2012-01-01
Start Page:	e51563
Language:	English
DOI:	10.1371/journal.pone.0051563
PROVIDER:	scopus
PMCID:	PMC3520950
PUBMED:	23251575
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84871229659&partnerID=40&md5=2d403d9565207b81ce976c9c39b4763b
Notes:	--- - "Export Date: 2 January 2013" - "Source: Scopus"

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