Hydrogen peroxide activates APE1/Ref-1 via NF-κB and Parkin: a role in liver cancer resistance to oxidative stress

Cancer cells exhibit an altered redox balance and aberrant redox signaling due to genetic, metabolic, and microenvironment-associated reprogramming. Persistently elevated levels of reactive oxygen species (ROS) contribute to many aspects of tumor development and progression. Emerging studies demonstrated the vital role of apurinic/apyrimidinic endonuclease 1 or reduction/oxidation (redox) factor 1(APE1/Ref-1) in the oxidative stress response and survival of cancer cells. APE1/Ref-1 is a multifunctional enzyme involved in the DNA damage response and functions as a redox regulator of transcription factors. We herein demonstrated that basal hydrogen peroxide (H2O2) and APE1/Ref-1 expression levels were markedly higher in cancer cell lines than in non-cancerous cells. Elevated APE1/Ref-1 levels were associated with shorter survival in liver cancer patients. Mechanistically, we showed that H2O2 activated nuclear factor-κB (NF-κB). RelA/p65 inhibited the expression of the E3 ubiquitin ligase Parkin, possibly by interfering with ATF4 activity. Parkin was responsible for the ubiquitination and proteasomal degradation of APE1/Ref-1; therefore, the H2O2-induced suppression of Parkin expression increased APE1/Ref-1 levels. The probability of survival was lower in liver cancer patients with low Parkin and high RelA expression levels. Additionally, Parkin and RelA expression levels negatively and positively correlated with APE1/Ref-1 levels, respectively, in the TCGA liver cancer cohort. We concluded that increases in APE1/Ref-1 via the NF-κB and Parkin pathways are critical for cancer cell survival under oxidative stress. The present results show the potential of the NF-κB-Parkin-APE1/Ref-1 axis as a prognostic factor and therapeutic strategy to eradicate liver cancer.

[1]  S. Imaoka,et al.  Nrf2 and Parkin-Hsc70 regulate the expression and protein stability of p62/SQSTM1 under hypoxia , 2022, Scientific reports.

[2]  G. Tell,et al.  APE1 interacts with the nuclear exosome complex protein MTR4 and is involved in cisplatin‐ and 5‐fluorouracil‐induced RNA damage response , 2022, The FEBS journal.

[3]  E. Dalla,et al.  APE1 controls DICER1 expression in NSCLC through miR-33a and miR-130b , 2022, Cellular and Molecular Life Sciences.

[4]  S. Imaoka,et al.  Chlorogenic acid activates Nrf2/SKN-1 and prolongs the lifespan of Caenorhabditis elegans via the Akt-FOXO3/DAF16a-DDB1 pathway and activation of DAF16f. , 2022, The journals of gerontology. Series A, Biological sciences and medical sciences.

[5]  S. Imaoka,et al.  Yeast β-glucan increases etoposide sensitivity in lung cancer cell line A549 by suppressing Nrf2 via the non-canonical NF-κB pathway. , 2022, Molecular Pharmacology.

[6]  M. Minden,et al.  PRMT5 regulates ATF4 transcript splicing and oxidative stress response , 2022, bioRxiv.

[7]  G. Elizondo,et al.  Regulation of Parkin expression as the key balance between neural survival and cancer cell death. , 2021, Biochemical pharmacology.

[8]  G. Tell,et al.  Coping with RNA damage with a focus on APE1, a BER enzyme at the crossroad between DNA damage repair and RNA processing/decay. , 2021, DNA repair.

[9]  S. Imaoka,et al.  Sp1 is a substrate of Keap1 and regulates the activity of CRL4AWDR23 ubiquitin ligase toward Nrf2 , 2021, The Journal of biological chemistry.

[10]  N. Jha,et al.  Oxidative Stress in Cancer Cell Metabolism , 2021, Antioxidants.

[11]  Gang Zhou,et al.  Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy , 2021, Cancers.

[12]  J. Qian,et al.  Alternative splicing and cancer: a systematic review , 2021, Signal Transduction and Targeted Therapy.

[13]  J. Duszyński,et al.  Multitasking guardian of mitochondrial quality: Parkin function and Parkinson’s disease , 2021, Translational Neurodegeneration.

[14]  S. Imaoka,et al.  Feedback of hypoxia-inducible factor-1alpha (HIF-1alpha) transcriptional activity via redox factor-1 (Ref-1) induction by reactive oxygen species (ROS) , 2021, Free radical research.

[15]  Jing Chen,et al.  APEX1 regulates alternative splicing of key tumorigenesis genes in non-small-cell lung cancer , 2020, BMC Medical Genomics.

[16]  K. Tew,et al.  Oxidative Stress in Cancer. , 2020, Cancer cell.

[17]  J. Valcárcel,et al.  Roles and mechanisms of alternative splicing in cancer — implications for care , 2020, Nature Reviews Clinical Oncology.

[18]  Hongwei Cheng,et al.  APEX1 is a novel diagnostic and prognostic biomarker for hepatocellular carcinoma , 2020, Aging.

[19]  Yulan Zhao,et al.  Metformin rescues Parkin protein expression and mitophagy in high glucose-challenged human renal epithelial cells by inhibiting NF-κB via PP2A activation. , 2020, Life sciences.

[20]  Ihab Younis,et al.  The Cancer Spliceome: Reprograming of Alternative Splicing in Cancer , 2018, Front. Mol. Biosci..

[21]  H. Walden,et al.  Parkin function in Parkinson's disease , 2018, Science.

[22]  J. Klaunig,et al.  Oxidative stress in carcinogenesis , 2018 .

[23]  E. Dalla,et al.  Mammalian APE1 controls miRNA processing and its interactome is linked to cancer RNA metabolism , 2017, Nature Communications.

[24]  R. Messmann,et al.  Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic , 2017, npj Precision Oncology.

[25]  Cheng Li,et al.  GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses , 2017, Nucleic Acids Res..

[26]  C. Horbinski,et al.  Polyubiquitination of apurinic/apyrimidinic endonuclease 1 by Parkin , 2017, Molecular carcinogenesis.

[27]  C. Vascotto,et al.  Transcriptional Up-Regulation of APE1/Ref-1 in Hepatic Tumor: Role in Hepatocytes Resistance to Oxidative Stress and Apoptosis , 2015, PloS one.

[28]  Y. Seo,et al.  Human AP Endonuclease 1: A Potential Marker for the Prediction of Environmental Carcinogenesis Risk , 2014, Oxidative medicine and cellular longevity.

[29]  A. Mantha,et al.  APE1/Ref-1 as an emerging therapeutic target for various human diseases: phytochemical modulation of its functions , 2014, Experimental & Molecular Medicine.

[30]  Jiangning Song,et al.  hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties. , 2013, Biochimica et biophysica acta.

[31]  Steven P. Gygi,et al.  Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization , 2013, Nature.

[32]  I. Mahjabeen,et al.  Genetic and expressional variations of APEX1 are associated with increased risk of head and neck cancer. , 2013, Mutagenesis.

[33]  Y. Watarai,et al.  Apurinic/apyrimidinic endonuclease-1 (APE-1) is overexpressed via the activation of NF-κB-p65 in MCP-1-positive esophageal squamous cell carcinoma tissue , 2013, Journal of clinical biochemistry and nutrition.

[34]  C. Xiong,et al.  Silencing of APE1 Enhances Sensitivity of Human Hepatocellular Carcinoma Cells to Radiotherapy In Vitro and in a Xenograft Model , 2013, PloS one.

[35]  A. Heydari,et al.  DNA Repair and Cancer Therapy: Targeting APE1/Ref-1 Using Dietary Agents , 2012, Journal of oncology.

[36]  G. Dianov,et al.  Ubiquitin ligase UBR3 regulates cellular levels of the essential DNA repair protein APE1 and is required for genome stability , 2011, Nucleic acids research.

[37]  M. Goldberg,et al.  Lipopolysaccharide and Tumor Necrosis Factor Regulate Parkin Expression via Nuclear Factor-Kappa B , 2011, PloS one.

[38]  Yong-Zi Chen,et al.  Prediction of Ubiquitination Sites by Using the Composition of k-Spaced Amino Acid Pairs , 2011, PloS one.

[39]  S. Lipton,et al.  Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation , 2011, Molecular Neurodegeneration.

[40]  David S. Park,et al.  Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress , 2011, Cell Death and Differentiation.

[41]  C. Avellini,et al.  Apurinic apyrimidinic endonuclease/redox effector factor 1 immunoreactivity and grading in hepatocellular carcinoma risk of relapse after liver transplantation. , 2010, Transplantation proceedings.

[42]  A. Nardulli,et al.  Immunohistochemical analysis of oxidative stress and DNA repair proteins in normal mammary and breast cancer tissues , 2010, BMC Cancer.

[43]  T. Kawai,et al.  Oxidative stress-induced alternative splicing of transformer 2beta (SFRS10) and CD44 pre-mRNAs in gastric epithelial cells. , 2009, American journal of physiology. Cell physiology.

[44]  E. Friedberg,et al.  Oxidative stress alters base excision repair pathway and increases apoptotic response in apurinic/apyrimidinic endonuclease 1/redox factor-1 haploinsufficient mice. , 2009, Free radical biology & medicine.

[45]  G. Tell,et al.  The many functions of APE1/Ref-1: not only a DNA repair enzyme. , 2009, Antioxidants & redox signaling.

[46]  T. Iwakuma,et al.  Ubiquitination of mammalian AP endonuclease (APE1) regulated by the p53-MDM2 signaling pathway , 2009, Oncogene.

[47]  Yang Zhang,et al.  Silencing of Ref-1 Expression by Retrovirus-Mediated shRNA Sensitizes HEK293 Cells to Hydrogen Peroxide-Induced Apoptosis , 2008, Bioscience, biotechnology, and biochemistry.

[48]  R. Takahashi,et al.  Parkin as a tumor suppressor gene for hepatocellular carcinoma , 2008, Oncogene.

[49]  S. Gustincich,et al.  APE1/Ref-1 regulates PTEN expression mediated by Egr-1 , 2008, Free radical research.

[50]  V. Carraro,et al.  The p300/CBP-associated factor (PCAF) is a cofactor of ATF4 for amino acid-regulated transcription of CHOP , 2007, Nucleic acids research.

[51]  C. Theriot,et al.  Analysis of nuclear transport signals in the human apurinic/apyrimidinic endonuclease (APE1/Ref1) , 2005, Nucleic acids research.

[52]  G. Tell,et al.  The intracellular localization of APE1/Ref-1: more than a passive phenomenon? , 2005, Antioxidants & redox signaling.

[53]  Takashi Uehara,et al.  Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Fang Wang,et al.  Parkin gene alterations in hepatocellular carcinoma , 2004, Genes, chromosomes & cancer.

[55]  G. Tell,et al.  An 'environment to nucleus' signaling system operates in B lymphocytes: redox status modulates BSAP/Pax-5 activation through Ref-1 nuclear translocation. , 2000, Nucleic acids research.

[56]  G. Haegeman,et al.  The Nuclear Factor-κB Engages CBP/p300 and Histone Acetyltransferase Activity for Transcriptional Activation of the Interleukin-6 Gene Promoter* , 1999, The Journal of Biological Chemistry.

[57]  C. Ramana,et al.  Activation of apurinic/apyrimidinic endonuclease in human cells by reactive oxygen species and its correlation with their adaptive response to genotoxicity of free radicals. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[58]  S. Mitra,et al.  Negative regulation of the major human AP-endonuclease, a multifunctional protein. , 1996, Biochemistry.

[59]  B. Demple,et al.  Characterization of the Promoter Region of the Human Apurinic Endonuclease Gene (APE) (*) , 1995, The Journal of Biological Chemistry.

[60]  Michael J Morgan,et al.  Crosstalk of reactive oxygen species and NF-κB signaling , 2011, Cell Research.