The DNA base excision repair protein Ape1/Ref-1 as a therapeutic and chemopreventive target

Fishel, Melissa L.; Kelley, Mark R.

doi:10.1016/j.mam.2007.04.005

Cited by 248 publications

(258 citation statements)

References 105 publications

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“…Our results are supported by those of others in that the suppression of APE1 results in hypersensitivity to chemotherapeutic agents (10,26,27). Additionally, targeted reduction of Ape1/Ref-1 protein by specific anti-sense oligonucleotides renders mammalian cells hypersensitive to methylmethane sulfonate (MMS), H 2 O 2 , bleomycin, temozolomide (TMZ) and gemcitabine (22,28,29). Moreover, Robertson and colleagues found that elevated expression of APE1 in testicular cancer cell lines results in resistance to certain therapeutic agents, such as bleomycin and radiation (21).…”

Section: Cell Cycle Perturbations Aftersupporting

confidence: 87%

“…Several studies have focused on some small molecules that blocked APE1 DNA repair function or its redox function, respectively, to explore the effect of APE1 or Ref-1 on the cancer cell response to chemotherapeutic agents and radiotherapy. It has emerged that some small molecules blocked APE1/Ref-1 DNA repair function, or its redox function, such as methoxyamine (MX) and 7-nitroindole-2-carboxylic acid (NCA), indirect and direct inhibitor of APE1/Ref-1's DNA repair activity, respectively, and lucanthone, direct inhibitor of APE1/Ref-1 repair activity (28). For example, lucanthone sensitizes breast cancer cells to methylating agents (38).…”

Section: Cell Cycle Perturbations Aftermentioning

confidence: 99%

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Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) in human ovarian cancer and indentification of the therapeutic potential of APE1/Ref-1 inhibitor

Zhang

Wang²,

Xiang³

et al. 2009

Int J Oncol

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Abstract.Resistance to platinum is a major limitation for the treatment of ovarian cancer. In an effort to overcome the platinum resistance problem in ovarian cancer treatment, we explored the correlation between cisplatin resistance and the human AP endonuclease (APE1 or Ref-1). APE1/Ref-1 is a multifunctional protein that is not only an essential enzyme in base excision repair pathway, but also acts as a major redox-signaling factor that has a wide variety of important cellular functions including transcription factor regulation, oxidative signaling and cell cycle control. In this study, we

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Section: Cell Cycle Perturbations Aftersupporting

confidence: 87%

Section: Cell Cycle Perturbations Aftermentioning

confidence: 99%

Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) in human ovarian cancer and indentification of the therapeutic potential of APE1/Ref-1 inhibitor

Zhang

Wang²,

Xiang³

et al. 2009

Int J Oncol

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“…[4][5][6] In particular, APE1 is becoming a leading target due to its central involvement in DNA repair signaling. 31 The BER pathway is essential for the removal of DNA bases damaged by alkylation or oxidation. A key step in BER is the processing of an AP site intermediate by an AP endonuclease.…”

Section: Discussionmentioning

confidence: 99%

Chimeric adenoviral vector Ad5/F35-mediated APE1 siRNA enhances sensitivity of human colorectal cancer cells to radiotherapy in vitro and in vivo

Wang

et al. 2008

Cancer Gene Ther

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Apurinic/apyrimidinic endonuclease (APE1), a bifunctional AP endonuclease/redox factor, is important in DNA repair and redox signaling, may be associated with radioresistance. Here we investigate whether targeted inhibition of APE1 can sensitize tumor cells to irradiation in vitro and in vivo. We first constructed chimeric adenoviral vector Ad5/F35 carrying human APE1 siRNA (Ad5/ F35-APE1 siRNA). The infectivity of chimeric Ad5/F35 to LOVO colon cancer cells was greater than that of Ad5. APE1 was strongly expressed and nuclear factor kB (NF-kB), a downstream molecule of APE1, known as a radioresistance factor, was constitutively active in LOVO cells. Infection of LOVO cells with Ad5/F35-APE1 siRNA resulted in a dose-dependent decrease of APE1 protein and AP endonuclease activity in vitro. Ad5/F35-APE1 siRNA significantly enhanced sensitivity of LOVO cells to irradiation in clonogenic survival assays, associated with increased cell apoptosis. The APE1 expression in LOVO cells was induced by irradiation in a dose-dependent manner, accompanied with the enhancement of DNA-binding activity of NF-kB and Ad5/F35-APE1 siRNA effectively inhibited constitutive and irradiation-induced APE1 expression and NF-kB activation. In a subcutaneous nude mouse colon cancer model, Ad5/F35-APE1 siRNA (5 Â 10 8 IU, intratumoral injection) inhibited the expression of APE1 protein in LOVO xenografts, and significantly enhanced inhibition of tumor growth by irradiation. In conclusion, APE1 may be involved as one of the radioresistance factors, and targeted inhibition of APE1 shows an effective means of enhancing tumor sensitivity to radiotherapy.

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“…Based on its involvement in cancer, and its regulation of several transcription factors associated with cancer‐related pathways, APE1 has become a prime target for anticancer therapies (Fishel and Kelley, 2007; Kelley et al ., 2014). Particular interest has been assigned to determining the different genes and pathways affected by APE1.…”

Section: Introductionmentioning

confidence: 99%

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

et al. 2017

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Apurinic/apyrimidinic endonuclease 1/redox factor‐1 (APE1/Ref‐1 or APE1) is a multifunctional protein that regulates numerous transcription factors associated with cancer‐related pathways. Because APE1 is essential for cell viability, generation of APE1‐knockout cell lines and determining a comprehensive list of genes regulated by APE1 has not been possible. To circumvent this challenge, we utilized single‐cell RNA sequencing to identify differentially expressed genes (DEGs) in relation to APE1 protein levels within the cell. Using a straightforward yet novel statistical design, we identified 2837 genes whose expression is significantly changed following APE1 knockdown. Using this gene expression profile, we identified multiple new pathways not previously linked to APE1, including the EIF2 signaling and mechanistic target of Rapamycin pathways and a number of mitochondrial‐related pathways. We demonstrate that APE1 has an effect on modifying gene expression up to a threshold of APE1 expression, demonstrating that it is not necessary to completely knockout APE1 in cells to accurately study APE1 function. We validated the findings using a selection of the DEGs along with siRNA knockdown and qRT‐PCR. Testing additional patient‐derived pancreatic cancer cells reveals particular genes (ITGA1,TNFAIP2,COMMD7,RAB3D) that respond to APE1 knockdown similarly across all the cell lines. Furthermore, we verified that the redox function of APE1 was responsible for driving gene expression of mitochondrial genes such as PRDX5 and genes that are important for proliferation such as SIPA1 and RAB3D by treating with APE1 redox‐specific inhibitor, APX3330. Our study identifies several novel genes and pathways affected by APE1, as well as tumor subtype specificity. These findings will allow for hypothesis‐driven approaches to generate combination therapies using, for example, APE1 inhibitor APX3330 with other approved FDA drugs in an innovative manner for pancreatic and other cancer treatments.

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The DNA base excision repair protein Ape1/Ref-1 as a therapeutic and chemopreventive target

Cited by 248 publications

References 105 publications

Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) in human ovarian cancer and indentification of the therapeutic potential of APE1/Ref-1 inhibitor

Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) in human ovarian cancer and indentification of the therapeutic potential of APE1/Ref-1 inhibitor

Chimeric adenoviral vector Ad5/F35-mediated APE1 siRNA enhances sensitivity of human colorectal cancer cells to radiotherapy in vitro and in vivo

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

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