APE1 overexpression is associated with cisplatin resistance in non-small cell lung cancer and targeted inhibition of APE1 enhances the activity of cisplatin in A549 cells

Wang, Dong; Xiang, Dingcheng; Yang, Xueqin; Chen, Liansheng; Li, Mengxia; Zhong, Zhaoyang; Zhang, Yunsong

doi:10.1016/j.lungcan.2009.02.019

Cited by 157 publications

(176 citation statements)

References 29 publications

(36 reference statements)

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“…Our study is consistent with recent preclinical observations using melanoma cell lines where APE1 overexpression conferred protection from cisplatin (Yang et al, 2005). Moreover, in lung cancer, blocking APE1 function potentiated cisplatin cytotoxicity (Wang et al, 2009). These studies imply that APE1 is involved in the repair of damage induced by platinating agents, and current evidence suggests that the protective effect may be contributed by the DNA repair as well as the redoxregulatory activity of APE1.…”

Section: Discussionsupporting

confidence: 92%

Human apurinic/apyrimidinic endonuclease (APE1) is a prognostic factor in ovarian, gastro-oesophageal and pancreatico-biliary cancers

et al. 2010

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BACKGROUND: Altered DNA repair may be associated with aggressive tumour biology and impact upon response to chemotherapy and radiotherapy. We investigated whether expression of human AP endonuclease (APE1), a key multifunctional protein involved in DNA BER, would impact on clinicopathological outcomes in ovarian, gastro-oesophageal, and pancreatico-biliary cancer. METHODS: Formalin-fixed human ovarian, gastro-oesophageal, and pancreatico-biliary cancers were constructed into TMAs. Expression of APE1 was analysed by IHC and correlated to clinicopathological variables. RESULTS: In ovarian cancer, nuclear APE1 expression was seen in 71.9% (97 out of 135) of tumours and correlated with tumour type (P ¼ 0.006), optimal debulking (P ¼ 0.009), and overall survival (P ¼ 0.05). In gastro-oesophageal cancers previously exposed to neoadjuvant chemotherapy, 34.8% (16 out of 46) of tumours were positive in the nucleus and this correlated with shorter overall survival (P ¼ 0.005), whereas cytoplasmic localisation correlated with tumour dedifferentiation (P ¼ 0.034). In pancreatico-biliary cancer, nuclear staining was seen in 44% (32 out of 72) of tumours. Absence of cytoplasmic staining was associated with perineural invasion (P ¼ 0.007), vascular invasion (P ¼ 0.05), and poorly differentiated tumours (P ¼ 0.068). A trend was noticed with advanced stage (P ¼ 0.077). CONCLUSIONS: Positive clinicopathological correlations of APE1 expression suggest that APE1 is a potential drug target in ovarian, gastro-oesophageal, and pancreatico-biliary cancers.

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Section: Discussionsupporting

confidence: 92%

Human apurinic/apyrimidinic endonuclease (APE1) is a prognostic factor in ovarian, gastro-oesophageal and pancreatico-biliary cancers

et al. 2010

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“…Hyper-sensitivity of APE1 KD cells has been reported for other clinical DNA-damaging agents, including ionizing radiation (32,150,237), bleomycin (56,170,218), gemcitabine (239), cisplatin (222,246), etoposide (185,221), and photodynamic therapy (236,243). While in some cases it is not obvious what role APE1 would play in repairing the direct DNA damage (e.g., for the crosslinking agent cisplatin), some level of oxidative stress is involved in most genotoxin exposures.…”

Section: Protein Depletionmentioning

confidence: 99%

Human Apurinic/Apyrimidinic Endonuclease 1

2014

Antioxidants & Redox Signaling

228

221

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Significance: Human apurinic/apyrimidinic endonuclease 1 (APE1, also known as REF-1) was isolated based on its ability to cleave at AP sites in DNA or activate the DNA binding activity of certain transcription factors. We review herein topics related to this multi-functional DNA repair and stress-response protein. Recent Advances: APE1 displays homology to Escherichia coli exonuclease III and is a member of the divalent metal-dependent a/b fold-containing phosphoesterase superfamily of enzymes. APE1 has acquired distinct active site and loop elements that dictate substrate selectivity, and a unique N-terminus which at minimum imparts nuclear targeting and interaction specificity. Additional activities ascribed to APE1 include 3¢-5¢ exonuclease, 3¢-repair diesterase, nucleotide incision repair, damaged or site-specific RNA cleavage, and multiple transcription regulatory roles. Critical Issues: APE1 is essential for mouse embryogenesis and contributes to cell viability in a genetic background-dependent manner. Haploinsufficient APE1 +/ -mice exhibit reduced survival, increased cancer formation, and cellular/tissue hyper-sensitivity to oxidative stress, supporting the notion that impaired APE1 function associates with disease susceptibility. Although abnormal APE1 expression/localization has been seen in cancer and neuropathologies, and impaired-function variants have been described, a causal link between an APE1 defect and human disease remains elusive. Future Directions: Ongoing efforts aim at delineating the biological role(s) of the different APE1 activities, as well as the regulatory mechanisms for its intra-cellular distribution and participation in diverse molecular pathways. The determination of whether APE1 defects contribute to human disease, particularly pathologies that involve oxidative stress, and whether APE1 small-molecule regulators have clinical utility, is central to future investigations. Antioxid. Redox Signal. 20,

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“…The involvement of BER has also been demonstrated in the lesion bypass of cisplatin DNA adducts (14,15). This has clinical relevance as many cancer types have been shown to have deregulated BER protein levels (11,16,17). An Oncomine TM (Compendia Bioscience, Ann Arbor, MI) search revealed that cisplatin-resistant cells display enhanced as well as reduced expression of BER proteins in tumor samples and cancer cells.…”

mentioning

confidence: 99%

“…The ICL DNA repair pathways have been shown to be both replication-dependent (8) and replication-independent (9). Recent evidence suggests a possible role of BER in ICL repair (10), where targeting BER showed enhanced sensitivity to cross-linking agents such as cisplatin, mitomycin C, and psoralen (11)(12)(13). The involvement of BER has also been demonstrated in the lesion bypass of cisplatin DNA adducts (14,15).…”

mentioning

confidence: 99%

Novel Role of Base Excision Repair in Mediating Cisplatin Cytotoxicity

Kothandapani

Dangeti

Brown

et al. 2011

Journal of Biological Chemistry

121

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Using isogenic mouse embryonic fibroblasts and human cancer cell lines, we show that cells defective in base excision repair (BER) display a cisplatin-specific resistant phenotype. This was accompanied by enhanced repair of cisplatin interstrand crosslinks (ICLs) and ICL-induced DNA double strand breaks, but not intrastrand adducts. Cisplatin induces abasic sites with a reduced accumulation in uracil DNA glycosylase (UNG) null cells. We show that cytosines that flank the cisplatin ICLs undergo preferential oxidative deamination in vitro, and AP endonuclease 1 (APE1) can cleave the resulting ICL DNA substrate following removal of the flanking uracil. We also show that DNA polymerase ␤ has low fidelity at the cisplatin ICL site after APE1 incision. Down-regulating ERCC1-XPF in BER-deficient cells restored cisplatin sensitivity. Based on our results, we propose a novel model in which BER plays a positive role in maintaining cisplatin cytotoxicity by competing with the productive cisplatin ICL DNA repair pathways.

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APE1 overexpression is associated with cisplatin resistance in non-small cell lung cancer and targeted inhibition of APE1 enhances the activity of cisplatin in A549 cells

Cited by 157 publications

References 29 publications

Human apurinic/apyrimidinic endonuclease (APE1) is a prognostic factor in ovarian, gastro-oesophageal and pancreatico-biliary cancers

Human apurinic/apyrimidinic endonuclease (APE1) is a prognostic factor in ovarian, gastro-oesophageal and pancreatico-biliary cancers

Human Apurinic/Apyrimidinic Endonuclease 1

Novel Role of Base Excision Repair in Mediating Cisplatin Cytotoxicity

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