PARP inhibition versus PARP-1 silencing: different outcomes in terms of single-strand break repair and radiation susceptibility

Godon, Camille; Cordelières, Fabrice P.; Biard, Denis; Giocanti, Nicole; Mégnin-Chanet, Frédérique; Hall, Janet; Favaudon, Vincent

doi:10.1093/nar/gkn403

Cited by 165 publications

(195 citation statements)

References 53 publications

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“…Based on in vitro experimental evidence, 14,15 it has been suggested that the greatest therapeutic benefit a PARP inhibitor combined with radiotherapy would be seen in cells that are rapidly dividing as the greatest relative impact on cell killing from this combined treatment was seen in S-phase cells. In order to investigate whether transcript levels were modulated under these circumstances, we studied their correlation with the transcript level of the nuclear proliferative marker MKI67.…”

Section: Tumors While Those Tumors Having An Underexpression Have Thementioning

confidence: 99%

Variations in the mRNA expression of poly(ADP‐ribose) polymerases, poly(ADP‐ribose) glycohydrolase and ADP‐ribosylhydrolase 3 in breast tumors and impact on clinical outcome

Bièche

Pennaneach

Driouch

et al. 2013

Intl Journal of Cancer

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In order to assess the variation in expression of poly(ADP-ribose) polymerase (PARP) family members and the hydrolases that degrade the poly(ADP-ribose) polymers they generate and possible associations with classical pathological parameters, including long-term outcome, the mRNA levels of PARP1, PARP2, PARP3, poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosylhydrolase 3 (ARH3) were examined using quantitative reverse transcription polymerase chain reaction in 443 unilateral invasive breast cancers and linked to hormonal status, tumor proliferation and clinical outcome. PARP1 mRNA levels were the highest among these five genes in both normal and tumor tissues, with a 2.45-fold higher median level in tumors compared to normal tissues. Tumors (34.1%) showed PARP1 overexpression (>3 fold relative to normal breast tissues) compared to underexpression (<0.33 fold) in only 0.5%. This overexpression was seen in all breast tumor subgroups, with the highest fraction (51%) seen in the HR-positive/ERBB2-positive subgroup and was not highly associated with any other classical predictive factors. No correlation was seen between PARP1 mRNA and PARP-1 protein levels in a subset of 31 tumors. PARP3 was underexpressed in 10.4% of tumors, more frequently in the HR-negative tumors (25.4%) than the HR-positive tumors (5.9%). This PARP3 underexpression was mutually exclusive with a PARP1 overexpression. PARP2 levels were unchanged between normal and tumor tissues and few tumors showed overexpression of PARG (3.8%) or ARH3 (3.4%). Within the subgroup of triple negative tumors, PARG mRNA levels below the median were associated with a higher risk of developing metastases (p 5 0.039) raising the possibility this might be marker of clinical outcome.

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Section: Tumors While Those Tumors Having An Underexpression Have Thementioning

confidence: 99%

Variations in the mRNA expression of poly(ADP‐ribose) polymerases, poly(ADP‐ribose) glycohydrolase and ADP‐ribosylhydrolase 3 in breast tumors and impact on clinical outcome

Bièche

Pennaneach

Driouch

et al. 2013

Intl Journal of Cancer

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“…Additionally, it has been shown that PARP-1 -/-knockout mice are more sensitive to radiation than wildtype mice [102]. In addition to knockout mice, studies examining the effect of PARP silencing using RNA interference have been effective in reduction of PARP and PARP activity and have increased radiosensitivity in a manner equivalent to PARP-1 -/-knockout mice [103]. In our hands, silencing of PARP-1 in glioblastoma cell lines was generally not as effective as treatment with a PARP inhibitor [104].…”

Section: Inhibitors Versus Deletion or Silencingmentioning

confidence: 99%

Targeting DNA Repair Mechanisms to Treat Glioblastoma

Lawrence¹,

Bammert²,

Belton³

et al. 2015

Advances in DNA Repair

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“…Next, we evaluated the effects of PARP inhibition on the ability of cancer cells to repair DNA SSBs, which are the most common type of DNA damage and are primarily repaired by base excision repair, a process catalyzed by PARP-1 through the formation of (PAR) chains (32)(33)(34)(35). It has previously been shown that the use of PARP inhibition leads to the accumulation of SSBs (12,36). We looked to evaluate whether the use of PARPi would lead to an increase in SSBs in JHU006 and JHU012 HNSCC cell lines.…”

Section: Parp Inhibition Induces Ssbs In Hnscc Cell Linesmentioning

confidence: 99%

Dual Disruption of DNA Repair and Telomere Maintenance for the Treatment of Head and Neck Cancer

Lajud

Nagda

Yamashita

et al. 2014

Clinical Cancer Research

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Purpose: Poly(ADP-ribose) polymerases (PARP) and the Mre11, Rad50, and Nbs1 (MRN) complex are key regulators of DNA repair, and have been recently shown to independently regulate telomere length. Sensitivity of cancers to PARPi is largely dependent on the BRCAness of the cells. Unfortunately, the vast majority of cancers are BRCA-proficient. In this study, therefore, we investigated whether a targeted molecular "hit" on the MRN complex, which is upstream of BRCA, can effectively sensitize BRCA-proficient head and neck squamous cell carcinoma (HNSCC) to PARP inhibitor (PARPi).Experimental Design: Human HNSCC cell lines and a mouse model with HNSCC xenografts were used in this study. In vitro and in vivo studies were conducted to evaluate the effects and underlying mechanisms of dual molecular disruption of PARP and the MRN complex, using a pharmacologic inhibitor and a dominant-negative Nbs1 expression vector, respectively.Results: Our findings demonstrate that downregulation of the MRN complex disrupts homologous recombination, and, when combined with PARPi, leads to accumulation of lethal DNA double-strand breaks. Moreover, we show that PARPi and MRN complex disruption induces significantly shortening telomere length. Together, our results demonstrate that dual disruption of these pathways causes significant cell death in BRCA-proficient tumor cells both in vitro and in vivo.Conclusion: Our study, for the first time, elucidates a novel mechanism for MRN complex and PARP inhibition beyond DNA repair, demonstrating the feasibility of a dual disruption approach that extends the utility of PARPi to the treatment of BRCA-proficient cancers. Clin Cancer Res; 20(24); 6465-78. Ó2014 AACR.

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PARP inhibition versus PARP-1 silencing: different outcomes in terms of single-strand break repair and radiation susceptibility

Cited by 165 publications

References 53 publications

Variations in the mRNA expression of poly(ADP‐ribose) polymerases, poly(ADP‐ribose) glycohydrolase and ADP‐ribosylhydrolase 3 in breast tumors and impact on clinical outcome

Variations in the mRNA expression of poly(ADP‐ribose) polymerases, poly(ADP‐ribose) glycohydrolase and ADP‐ribosylhydrolase 3 in breast tumors and impact on clinical outcome

Targeting DNA Repair Mechanisms to Treat Glioblastoma

Dual Disruption of DNA Repair and Telomere Maintenance for the Treatment of Head and Neck Cancer

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