PARP1 Is Overexpressed in Nasopharyngeal Carcinoma and Its Inhibition Enhances Radiotherapy

Abstract

Nasopharyngeal carcinoma is a rare but highly invasive cancer. As options of agents for effective combination chemoradiotherapy for advanced nasopharyngeal carcinoma are limited, novel therapeutic approaches are desperately needed. The ubiquitin ligase CHFR is known to target PARP1 for degradation and is epigenetically inactivated in nasopharyngeal carcinoma. We present evidence that PARP1 protein is indeed overexpressed in nasopharyngeal carcinoma cells in comparison with immortalized normal nasopharyngeal epithelial cells. Tissue microarray analysis also indicated that PARP1 protein is significantly elevated in primary nasopharyngeal carcinoma tissues, with strong correlation with all stages of nasopharyngeal carcinoma development. We found that the PARP inhibitor AZD2281 (olaparib) increased DNA damage, cell-cycle arrest, and apoptosis in nasopharyngeal carcinoma cells challenged with ionizing radiation or temozolomide. Isobologram analysis confirmed that the cytotoxicity triggered by AZD2281 and DNAdamaging agents was synergistic. Finally, AZD2281 also enhanced the tumor-inhibitory effects of ionizing radiation in animal xenograft models. These observations implicate that PARP1 overexpression is an early event in nasopharyngeal carcinoma development and provide a molecular basis of using PARP inhibitors to potentiate treatment of nasopharyngeal carcinoma with radio-and chemotherapy.

Strong KDM4B and KDM4D Expression Associates with Radioresistance and Aggressive Phenotype in Classical Hodgkin Lymphoma

“…Since there are already PARP inhibitors in the clinical use of solid malignancies (15), it might offer an interesting possibility to control the development of radioresistance. In favor of this, a recent study also demonstrated that inhibiting PARP1 enhances radiotherapy responses in nasopharyngeal carcinoma (16). If similar results could be found in lymphomas and the results presented here are confirmed in independent studies, the role of PARP inhibitors could be tested in the KDM4D-overexpressing subpopulations of Hodgkin lymphoma.…”

WITHDRAWN: An analysis of the gene interaction networks identifying the role of PARP1 in metastasis of non-small cell lung cancer

“…PARP1 played an important role in DNA damage repair, [15][16][17], which made PARP1 a valuable therapeutic target in the research of disease drug. Recently, it was found that PARP1 presented high expression in a series of cancers, which provided a high-value target for the study of tumor detection, stage and biological characteristics [18][19][20][21][22][23]. The overexpression of PARP1 results from much DNA damage in cancer cells with unstable genes, instead of the induction of the activated specific carcinogenic pathway [24].…”

Opportunities and challenges of radiotherapy for treating cancer

“…37 Because radiation therapy itself exploits differences in repair capacity between tissues, that the combination of radiation with PARP inhibitors is effective against cancers that have BRCA, MRE11, and other DNA-repair-protein mutations is no surprise. [39][40][41][42][43][44] However, PARP-1 is also activated by oxidative and nitrative stress, and is a known cofactor for nuclear factor κB (NF-κB)-driven inflammatory gene expression; 45 radiosensitization by PARP inhibitors might also be the result of inhibition of this crucial survival pathway ( Figure 2). 46 Not surprisingly, many clinical trials of PARP inhibitors in combination with radiation therapy are ongoing.…”