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Quantitative Proteomic and Interaction Network Analysis of Cisplatin Resistance in HeLa Cells

By Juan D. Chavez, Michael R. Hoopmann, Chad R. Weisbrod, Kohji Takara and James E. Bruce


Cisplatin along with other platinum based drugs are some of the most widely used chemotherapeutic agents. However drug resistance is a major problem for the successful chemotherapeutic treatment of cancer. Current evidence suggests that drug resistance is a multifactorial problem due to changes in the expression levels and activity of a wide number of proteins. A majority of the studies to date have quantified mRNA levels between drug resistant and drug sensitive cell lines. Unfortunately mRNA levels do not always correlate with protein expression levels due to post-transcriptional changes in protein abundance. Therefore global quantitative proteomics screens are needed to identify the protein targets that are differentially expressed in drug resistant cell lines. Here we employ a quantitative proteomics technique using stable isotope labeling with amino acids in cell culture (SILAC) coupled with mass spectrometry to quantify changes in protein levels between cisplatin resistant (HeLa/CDDP) and sensitive HeLa cells in an unbiased fashion. A total of 856 proteins were identified and quantified, with 374 displaying significantly altered expression levels between the cell lines. Expression level data was then integrated with a network of protein-protein interactions, and biological pathways to obtain a systems level view of proteome changes which occur with cisplatin resistance. Several of these proteins have been previously implicated in resistance towards platinum-based and other drugs, while many represent new potential markers or therapeutic targets

Topics: Research Article
Publisher: Public Library of Science
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Provided by: PubMed Central

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  1. (1997). A comparison of selected mRNA and protein abundances in human liver.
  2. A guided tour of the Trans-Proteomic Pipeline.
  3. (2008). A review of the S100 proteins in cancer. European journal of surgical oncology:
  4. (2007). Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA.
  5. (2003). ATM, ATR and DNAPK: initiators of the cellular genotoxic stress responses.
  6. (2005). BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics
  7. (2008). Cathepsin D–many functions of one aspartic protease. Critical reviews in oncology/hematology 68:
  8. (1993). Cisplatin inhibits in vitro translation by preventing the formation of complete initiation complex.
  9. (1998). Cisplatin inhibits synthesis of ribosomal RNA in vivo.
  10. (2007). Cisplatin nephrotoxicity: a review. The American journal of the medical sciences 334:
  11. (2003). Cisplatin: mode of cytotoxic action and molecular basis of resistance.
  12. (1998). Cluster analysis and display of genome-wide expression patterns.
  13. (2003). Comparing protein abundance and mRNA expression levels on a genomic scale.
  14. (1999). Correlation between protein and mRNA abundance in yeast. Molecular and cellular biology 19: 1720–1730. The Proteome of Cisplatin Resistance
  15. (2003). Cytoscape: a software environment for integrated models of biomolecular interaction networks.
  16. (2009). DDB1 targets Chk1 to the Cul4 E3 ligase complex in normal cycling cells and in cells experiencing replication stress.
  17. (2008). DJ-1 decreases Bax expression through repressing p53 transcriptional activity.
  18. (2005). DJ-1, a novel regulator of the tumor suppressor PTEN.
  19. (1998). DNAdependent protein kinase acts upstream of p53 in response to DNA damage.
  20. (2004). Genome-wide identification of genes conferring resistance to the anticancer agents cisplatin, oxaliplatin, and mitomycin C.
  21. (2010). Glutathione transferase omega 1-1 (GSTO1-1) plays an anti-apoptotic role in cell resistance to cisplatin toxicity.
  22. (2007). Glycolysis in cancer: a potential target for therapy.
  23. (2007). High-speed data reduction, feature detection, and MS/MS spectrum quality assessment of shotgun proteomics data sets using high-resolution mass spectrometry.
  24. (2009). How common are extraribosomal functions of ribosomal proteins?
  25. (2006). Hyaluronan-CD44 promotes phospholipase C-mediated Ca2+ signaling and cisplatin resistance in head and neck cancer. Archives of otolaryngology–head & neck surgery 132:
  26. (2008). Hyaluronan: a constitutive regulator of chemoresistance and malignancy in cancer cells.
  27. Hypoxiainducible factor 1alpha determines gastric cancer chemosensitivity via modulation of p53 and NF-kappaB.
  28. (2001). Increased expression of peroxiredoxin II confers resistance to cisplatin.
  29. (2002). Inhibition of aldose reductase enhances HeLa cell sensitivity to chemotherapeutic drugs and involves activation of extracellular signal-regulated kinases.
  30. (2005). Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia.
  31. Interactome networks and human disease.
  32. (2005). Involvement of ABC transporters in chemosensitivity of human renal cell carcinoma, and regulation of MRP2 expression by conjugated bilirubin.
  33. (2008). Ku80 deletion suppresses spontaneous tumors and induces a p53-mediated DNA damage response.
  34. (2008). MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification.
  35. (2001). Mechanisms of resistance to cisplatin.
  36. (2005). Metastasis-associated protein S100A4 induces angiogenesis through interaction with Annexin II and accelerated plasmin formation.
  37. (2000). Modulation of paclitaxel resistance by annexin IV in human cancer cell lines.
  38. (2006). Molecular changes to HeLa cells on continuous exposure to cisplatin or paclitaxel. Cancer chemotherapy and pharmacology 58:
  39. (2004). Molecular signature linked to acquired resistance to cisplatin in esophageal cancer cells.
  40. (2006). Overexpression of aldose reductase in human cancer tissues. Medical science monitor: international medical journal of experimental and clinical research 12: CR525–529.
  41. (2011). Overexpression of biliverdin reductase enhances resistance to chemotherapeutics. Cancer letters 300:
  42. (2010). Overexpression of S100A4 in human cancer cell lines resistant to methotrexate.
  43. Peroxiredoxin 6 overexpression attenuates cisplatin-induced apoptosis in human ovarian cancer cells.
  44. (1999). Probability-based protein identification by searching sequence databases using mass spectrometry data.
  45. (2007). Proteins, drug targets and the mechanisms they control: the simple truth about complex networks.
  46. (2005). Regulation of MDR1 expression and drug resistance by a positive feedback loop involving hyaluronan, phosphoinositide 3-kinase, and ErbB2. The Journal of biological chemistry 280:
  47. (2000). S100 protein-annexin interactions: a model of the (Anx2-p11)(2) heterotetramer complex. Biochimica et biophysica acta 1498:
  48. (2007). S100A4 contributes to the suppression of BNIP3 expression, chemoresistance, and inhibition of apoptosis in pancreatic cancer.
  49. (2009). STRING 8–a global view on proteins and their functional interactions in 630 organisms.
  50. (2007). Tannock IF
  51. (2007). The resurgence of platinum-based cancer chemotherapy.
  52. (2003). The role of glutathione-S-transferase in anticancer drug resistance.
  53. (2003). The role of the CD44/ ezrin complex in cancer metastasis. Critical reviews in oncology/hematology 46:
  54. (2001). Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction.
  55. (2007). Use of comparative proteomics to identify potential resistance mechanisms in cancer treatment. Cancer treatment reviews 33:
  56. Yu Q CD44 attenuates activation of the hippo signaling pathway and is a prime therapeutic target for glioblastoma.