Cisplatin resistance associated with PARP hyperactivation

Judith Michels, Ilio Vitale, Lorenzo Galluzzi, Julien Adam, Ken Andre Olaussen, Oliver Kepp, Laura Senovilla, Ibtissam Talhaoui, Justine Guegan, David Pierre Enot, Monique Talbot, Angelique Robin, Philippe Girard, Cedric Orear, Delphine Lissa, Abdul Qader Sukkurwala, Pauline Garcia, Parviz Behnam-Motlagh, Kimitoshi Kohno, Gen Sheng Wu & 6 others Catherine Brenner, Philippe Dessen, Murat Saparbaev, Jean Charles Soria, Maria Castedo, Guido Kroemer

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

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 (PAKhigh)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.

Original languageEnglish
Pages (from-to)2271-2280
Number of pages10
JournalCancer Research
Volume73
Issue number7
DOIs
Publication statusPublished - Apr 1 2013

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Cisplatin
Apoptosis
Neoplasms
Heterografts
Non-Small Cell Lung Carcinoma
DNA Damage
Cell Death
Poly(ADP-ribose) Polymerase Inhibitors

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Michels, J., Vitale, I., Galluzzi, L., Adam, J., Olaussen, K. A., Kepp, O., ... Kroemer, G. (2013). Cisplatin resistance associated with PARP hyperactivation. Cancer Research, 73(7), 2271-2280. https://doi.org/10.1158/0008-5472.CAN-12-3000

Cisplatin resistance associated with PARP hyperactivation. / Michels, Judith; Vitale, Ilio; Galluzzi, Lorenzo; Adam, Julien; Olaussen, Ken Andre; Kepp, Oliver; Senovilla, Laura; Talhaoui, Ibtissam; Guegan, Justine; Enot, David Pierre; Talbot, Monique; Robin, Angelique; Girard, Philippe; Orear, Cedric; Lissa, Delphine; Sukkurwala, Abdul Qader; Garcia, Pauline; Behnam-Motlagh, Parviz; Kohno, Kimitoshi; Wu, Gen Sheng; Brenner, Catherine; Dessen, Philippe; Saparbaev, Murat; Soria, Jean Charles; Castedo, Maria; Kroemer, Guido.

In: Cancer Research, Vol. 73, No. 7, 01.04.2013, p. 2271-2280.

Research output: Contribution to journalArticle

Michels, J, Vitale, I, Galluzzi, L, Adam, J, Olaussen, KA, Kepp, O, Senovilla, L, Talhaoui, I, Guegan, J, Enot, DP, Talbot, M, Robin, A, Girard, P, Orear, C, Lissa, D, Sukkurwala, AQ, Garcia, P, Behnam-Motlagh, P, Kohno, K, Wu, GS, Brenner, C, Dessen, P, Saparbaev, M, Soria, JC, Castedo, M & Kroemer, G 2013, 'Cisplatin resistance associated with PARP hyperactivation', Cancer Research, vol. 73, no. 7, pp. 2271-2280. https://doi.org/10.1158/0008-5472.CAN-12-3000
Michels J, Vitale I, Galluzzi L, Adam J, Olaussen KA, Kepp O et al. Cisplatin resistance associated with PARP hyperactivation. Cancer Research. 2013 Apr 1;73(7):2271-2280. https://doi.org/10.1158/0008-5472.CAN-12-3000
Michels, Judith ; Vitale, Ilio ; Galluzzi, Lorenzo ; Adam, Julien ; Olaussen, Ken Andre ; Kepp, Oliver ; Senovilla, Laura ; Talhaoui, Ibtissam ; Guegan, Justine ; Enot, David Pierre ; Talbot, Monique ; Robin, Angelique ; Girard, Philippe ; Orear, Cedric ; Lissa, Delphine ; Sukkurwala, Abdul Qader ; Garcia, Pauline ; Behnam-Motlagh, Parviz ; Kohno, Kimitoshi ; Wu, Gen Sheng ; Brenner, Catherine ; Dessen, Philippe ; Saparbaev, Murat ; Soria, Jean Charles ; Castedo, Maria ; Kroemer, Guido. / Cisplatin resistance associated with PARP hyperactivation. In: Cancer Research. 2013 ; Vol. 73, No. 7. pp. 2271-2280.
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