TXNL1-XRCC1 pathway regulates cisplatin-induced cell death and contributes to resistance in human gastric cancer

Cisplatin is a cytotoxic platinum compound that triggers DNA crosslinking induced cell death, and is one of the reference drugs used in the treatment of several types of human cancers including gastric cancer. However, intrinsic or acquired drug resistance to cisplatin is very common, and leading to treatment failure. We have recently shown that reduced expression of base excision repair protein XRCC1 (X-ray repair cross complementing group1) in gastric cancerous tissues correlates with a significant survival benefit from adjuvant first-line platinum-based chemotherapy. In this study, we demonstrated the role of XRCC1 in repair of cisplatin-induced DNA lesions and acquired cisplatin resistance in gastric cancer by using cisplatin-sensitive gastric cancer cell lines BGC823 and the cisplatin-resistant gastric cancer cell lines BGC823/cis-diamminedichloridoplatinum(II) (DDP). Our results indicated that the protein expression of XRCC1 was significantly increased in cisplatin-resistant cells and independently contributed to cisplatin resistance. Irinotecan, another chemotherapeutic agent to induce DNA damaging used to treat patients with advanced gastric cancer that progressed on cisplatin, was found to inhibit the expression of XRCC1 effectively, and leading to an increase in the sensitivity of resistant cells to cisplatin. Our proteomic studies further identified a cofactor of 26S proteasome, the thioredoxin-like protein 1 (TXNL1) that downregulated XRCC1 in BGC823/DDP cells via the ubiquitin-proteasome pathway. In conclusion, the TXNL1-XRCC1 is a novel regulatory pathway that has an independent role in cisplatin resistance, indicating a putative drug target for reversing cisplatin resistance in gastric cancer.

[1]  G. Wani,et al.  Differential contributory roles of nucleotide excision and homologous recombination repair for enhancing cisplatin sensitivity in human ovarian cancer cells , 2011, Molecular Cancer.

[2]  Gang Li,et al.  JWA regulates XRCC1 and functions as a novel base excision repair protein in oxidative-stress-induced DNA single-strand breaks , 2009, Nucleic acids research.

[3]  J. R. Kelley,et al.  Gastric cancer epidemiology and risk factors. , 2003, Journal of clinical epidemiology.

[4]  E. Cho,et al.  The cAMP signaling system inhibits the repair of γ-ray-induced DNA damage by promoting Epac1-mediated proteasomal degradation of XRCC1 protein in human lung cancer cells. , 2012, Biochemical and biophysical research communications.

[5]  T. Dawson,et al.  Iduna is a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that regulates DNA damage , 2011, Proceedings of the National Academy of Sciences.

[6]  M. Galanski.  Recent developments in the field of anticancer platinum complexes. , 2006, Recent patents on anti-cancer drug discovery.

[7]  Joon-Oh Park,et al.  Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  J. Essigmann,et al.  Recognition of cisplatin adducts by cellular proteins. , 2001, Mutation research.

[9]  G. Dianov,et al.  CHIP-mediated degradation and DNA damage-dependent stabilization regulate base excision repair proteins. , 2008, Molecular cell.

[10]  Farin Kamangar,et al.  Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  D. V. Von Hoff,et al.  CK2 Inhibitor CX-4945 Suppresses DNA Repair Response Triggered by DNA-Targeted Anticancer Drugs and Augments Efficacy: Mechanistic Rationale for Drug Combination Therapy , 2012, Molecular Cancer Therapeutics.

[12]  D. Lebwohl,et al.  Clinical development of platinum complexes in cancer therapy: an historical perspective and an update. , 1998, European journal of cancer.

[13]  Yves Pommier,et al.  Association of XRCC1 and tyrosyl DNA phosphodiesterase (Tdp1) for the repair of topoisomerase I-mediated DNA lesions. , 2003, DNA repair.

[14]  E. Reed,et al.  Inhibition of Gli1 results in altered c-Jun activation, inhibition of cisplatin-induced upregulation of ERCC1, XPD and XRCC1, and inhibition of platinum–DNA adduct repair , 2012, Oncogene.

[15]  J. Turchi,et al.  Cisplatin Sensitizes Cancer Cells to Ionizing Radiation via Inhibition of Nonhomologous End Joining , 2005, Molecular Cancer Research.

[16]  R. Hartmann-Petersen,et al.  Thioredoxin Txnl1/TRP32 Is a Redox-active Cofactor of the 26 S Proteasome* , 2009, Journal of Biological Chemistry.

[17]  A. Duncan,et al.  Regulation of cisplatin resistance and homologous recombinational repair by the TFIIH subunit XPD. , 2002, Cancer research.

[18]  E. Morel,et al.  The Redox Sensor TXNL1 Plays a Regulatory Role in Fluid Phase Endocytosis , 2007, PloS one.

[19]  W. K. Myint,et al.  Examining the non-homologous repair process following cisplatin and radiation treatments , 2002, International journal of radiation biology.

[20]  Yan Zhou,et al.  Prognostic and Predictive Role of JWA and XRCC1 Expressions in Gastric Cancer , 2012, Clinical Cancer Research.

[21]  S. Tjulandin,et al.  A prognostic model in patients treated for metastatic gastric cancer with second-line chemotherapy. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[22]  J. Crowley,et al.  Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  J. Gustafsson,et al.  Characterization of human thioredoxin‐like‐1: Potential involvement in the cellular response against glucose deprivation , 2006, FEBS letters.

[24]  A. Vortmeyer,et al.  Comparative proteomic profiles of meningioma subtypes. , 2006, Cancer research.

[25]  M. Dolan,et al.  Molecular mechanisms of resistance and toxicity associated with platinating agents. , 2007, Cancer treatment reviews.

[26]  S. Elledge,et al.  The DNA damage response: making it safe to play with knives. , 2010, Molecular cell.

[27]  Jianwei Zhou,et al.  JWA is required for arsenic trioxide induced apoptosis in HeLa and MCF-7 cells via reactive oxygen species and mitochondria linked signal pathway. , 2008, Toxicology and applied pharmacology.

[28]  Thomas J. Smith,et al.  美国临床肿瘤学会Ⅳ期非小细胞肺癌化疗的临床实践指南更新 , 2010, Zhongguo fei ai za zhi = Chinese journal of lung cancer.

[29]  J. Ajani,et al.  Irinotecan/cisplatin in advanced, treated gastric or gastroesophageal junction carcinoma. , 2002, Oncology.

[30]  B. Teh,et al.  Role of eIF3a in regulating cisplatin sensitivity and in translational control of nucleotide excision repair of nasopharyngeal carcinoma. , 2011, Oncogene.

[31]  G. Scagliotti,et al.  Nucleotide excision repair pathways involved in Cisplatin resistance in non-small-cell lung cancer. , 2003, Cancer control : journal of the Moffitt Cancer Center.

[32]  M. A. Comendador,et al.  Relationships between cisplatin-induced adducts and DNA strand-breaks, mutation and recombination in vivo in somatic cells of Drosophila melanogaster, under different conditions of nucleotide excision repair. , 2012, Mutation research.

[33]  Carsten Denkert,et al.  Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis. , 2008, The Lancet. Oncology.

[34]  Claude Denham,et al.  Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  J. Ménissier-de murcia,et al.  XRCC1 is phosphorylated by DNA-dependent protein kinase in response to DNA damage , 2006, Nucleic acids research.

[36]  L. Mayer,et al.  Drug ratio–dependent antitumor activity of irinotecan and cisplatin combinations in vitro and in vivo , 2009, Molecular Cancer Therapeutics.

[37]  Thomas J. Smith,et al.  2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  J. Ajani,et al.  Preoperative induction of CPT‐11 and cisplatin chemotherapy followed by chemoradiotherapy in patients with locoregional carcinoma of the esophagus or gastroesophageal junction , 2004, Cancer.

[39]  Jianwei Zhou,et al.  JWA enhances As2O3-induced tubulin polymerization and apoptosis via p38 in HeLa and MCF-7 cells , 2011, Apoptosis.

[40]  L. Mullenders,et al.  Sealing of chromosomal DNA nicks during nucleotide excision repair requires XRCC1 and DNA ligase III alpha in a cell-cycle-specific manner. , 2007, Molecular cell.

[41]  Yasuo Ohashi,et al.  Benefit of Adjuvant Chemotherapy for Resectable Gastric Cancer , 2009 .

[42]  E. Ahmed,et al.  Parp1-XRCC1 and the repair of DNA double strand breaks in mouse round spermatids. , 2010, Mutation research.

[43]  L. Galluzzi,et al.  Molecular mechanisms of cisplatin resistance , 2012, Oncogene.

[44]  Y. Bang,et al.  Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial , 2012, The Lancet.