Exploiting base excision repair to improve therapeutic approaches for pancreatic cancer

Sharbeen, George; McCarroll, Joshua A.; Goldstein, David; Phillips, Phoebe A.

doi:10.3389/fnut.2015.00010

Cited by 25 publications

(20 citation statements)

References 137 publications

(126 reference statements)

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“…Apurinic/Apyrimidinic Endonuclease/Redox Factor-1 (APE1/Ref-1) is a multifunctional protein that is involved in responses to oxidative stress, acting on both oxidative and alkylative DNA damage (via its endonuclease activity in base excision repair) (17–19) and augmenting activity of various transcription factors (via its redox signaling) (20–23), as well as contributing to clearance of RNA with damaged bases (24). APE1/Ref-1 expression and redox activity are increased in PDAC tissue, and its upregulation increases tumor cell migration, proliferation, and survival (17, 23).…”

Section: Introductionmentioning

confidence: 99%

“…APE1/Ref-1 expression and redox activity are increased in PDAC tissue, and its upregulation increases tumor cell migration, proliferation, and survival (17, 23). We previously demonstrated that APE1/Ref-1 redox activity regulates several transcription factors involved in pancreatic cancer signaling, including HIF-1α, as well as STAT3, and NFκB (20, 21).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

Logsdon

Grimard

Luo

et al. 2016

Molecular Cancer Therapeutics

133

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Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including hypoxia, which creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. AP Endonuclease-1/Redox Effector Factor 1 (APE1/Ref-1) is a multi-functional protein possessing a DNA repair function in base excision repair and the ability to reduce oxidized transcription factors, enabling them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in survival mechanisms, tumor growth, and hypoxia signaling. Here, we explore the mechanisms underlying PDAC cell responses to hypoxia and modulation of APE1/Ref-1 redox signaling activity, which regulates the transcriptional activation of hypoxia inducible factor 1 alpha (HIF1α). Carbonic anhydrase IX (CA9) is regulated by HIF1α and functions as part of the cellular response to hypoxia to regulate intracellular pH, thereby promoting cell survival. We hypothesized that modulating APE1/Ref-1 function will block activation of downstream transcription factors, STAT3 and HIF1α, interfering with hypoxia-induced gene expression. We demonstrate APE1/Ref-1 inhibition in patient-derived and established PDAC cells results in decreased HIF1α–mediated induction of CA9. Furthermore, an ex vivo 3D tumor co-culture model demonstrates dramatic enhancement of APE1/Ref-1-induced cell killing upon dual-targeting of APE1/Ref-1 and CA9. Both APE1/Ref-1 and CA9 are under clinical development, therefore these studies have the potential to direct novel PDAC therapeutic treatment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

Logsdon

Grimard

Luo

et al. 2016

Molecular Cancer Therapeutics

133

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“…APE1 expression is increased in several cancers such as pancreatic (Jiang et al ., 2010), prostate (Kelley et al ., 2001), cervical (Xu et al ., 1997), gliomas (Bobola et al ., 2004), lung (Yoo et al ., 2008), bladder (Shin et al ., 2015), colon (Lou et al ., 2014), and ovarian cancers (Al‐Attar et al ., 2010; Zhang et al ., 2009), and this increase is associated with resistance to radiation and chemotherapy, leading to poorer patient prognosis (Sharbeen et al ., 2015). 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).…”

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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“…DNA bases by flap-endonuclease (FEN1) and PCNA (Sharbeen et al, 2015;Sokhansanj et al, 2002). In our results, significant up-regulation of osfen1 gene and ospcna in shoots was detected, where in roots it was contrary.…”

Section: Discussionmentioning

confidence: 52%

PCR analysis of genes involved in base excision repair (BER) pathway in rice seedlings exposed to trivalent chromium

2019

Appl Env Biotechnol

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The base excision repair (BER) pathway is an essential defense mechanism in plants against oxidative damage of DNA. Previous studies have reported that chromium (Cr) exposure causes oxidative stress and DNA damage due to accumulation of reactive oxygen species (ROS). In this study, hydroponic experiments were carried out to investigate expression of 21 candidate genes involved in BER pathway in rice seedlings exposed to Cr(III) using qRT-PCR analysis. Changes of H2O2 and O −• 2 content in rice tissues and the relative growth rate of rice seedlings were also determined. Results indicated that Cr(III) exposure caused dose-dependent inhibition on the relative growth rate of rice seedlings. H2O2 content in roots was significantly increased, while changes of H2O2 and O −• 2 content in shoots was consistent. PCR analysis showed that transcriptional changes of 21 selected candidate genes to Cr(III) exposure were tissue specific. BER pathway in roots was repressed by Cr(III) treatment but activated in shoots, suggesting that the BER pathway would play different roles in regulating and repairing DNA damage caused by Cr(III) exposure in different rice tissues.

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Exploiting base excision repair to improve therapeutic approaches for pancreatic cancer

Cited by 25 publications

References 137 publications

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

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

PCR analysis of genes involved in base excision repair (BER) pathway in rice seedlings exposed to trivalent chromium

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