title: The synthetic peptide CIGB-300 modulates CK2-dependent signaling pathways affecting the survival and chemoresistance of non-small cell lung cancer cell lines.
abstract: BACKGROUND
  Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer-related deaths worldwide. Up to 80% of cancer patients are classified as non-small-cell lung cancer (NSCLC) and cisplatin remains as the gold standard chemotherapy treatment, despite its limited efficacy due to both intrinsic and acquired resistance. The CK2 is a Ser/Thr kinase overexpressed in various types of cancer, including lung cancer. CIGB-300 is an antitumor peptide with a novel mechanism of action, since it binds to CK2 substrates thus preventing the enzyme activity. The aim of this work was to analyze theeffectsof CIGB-300treatmenttargeting CK2-dependent signaling pathways in NSCLCcell linesand whether it may help improve current chemotherapy treatment.
  
  
  METHODS
  The human NSCLC cell lines NCI-H125 and NIH-A549 were used. Tumor spheroids were obtained through the hanging-drop method. A cisplatin resistant A549 cell line was obtained by chronic administration of cisplatin. Cell viability, apoptosis, immunoblotting, immunofluorescence and luciferase reporter assays were used to assess CIGB-300 effects. A luminescent assay was used to monitor proteasome activity.
  
  
  RESULTS
  We demonstrated that CIGB-300 induces an anti-proliferative response both in monolayer- and three-dimensional NSCLC models, presenting rapid and complete peptide uptake. This effect was accompanied by the inhibition of the CK2-dependent canonical NF-κB pathway, evidenced by reduced RelA/p65 nuclear levels and NF-κB protein targets modulation in both lung cancer cell lines, as well as conditionally reduced NF-κB transcriptional activity. In addition, NF-κB modulation was associated with enhanced proteasome activity, possibly through its α7/C8 subunit. Neither the peptide nor a classical CK2 inhibitor affected cytoplasmic β-CATENIN basal levels. Given that NF-κB activation has been linked to cisplatin-induced resistance, we explored whether CIGB-300 could bring additional therapeutic benefits to the standard cisplatin treatment. We established a resistant cell line that showed higher p65 nuclear levels after cisplatin treatment as compared with the parental cell line. Remarkably, the cisplatin-resistant cell line became more sensitive to CIGB-300 treatment.
  
  
  CONCLUSIONS
  Our data provide new insights into CIGB-300 mechanism of action and suggest clinical potential on current NSCLC therapy.
authors.affiliation: Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo", Área Investigaciones, Av. San Martín 5481, Buenos Aires, Argentina.|CONICET, Buenos Aires, Argentina.
authors.forename: Stéfano M
authors.initials: SM
authors.lastname: Cirigliano
authors.affiliation: Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo", Área Investigaciones, Av. San Martín 5481, Buenos Aires, Argentina.|CONICET, Buenos Aires, Argentina.
authors.forename: María I
authors.initials: MI
authors.lastname: Díaz Bessone
authors.affiliation: Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo", Área Investigaciones, Av. San Martín 5481, Buenos Aires, Argentina.
authors.forename: Damián E
authors.initials: DE
authors.lastname: Berardi
authors.affiliation: Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo", Área Investigaciones, Av. San Martín 5481, Buenos Aires, Argentina.
authors.forename: Carolina
authors.initials: C
authors.lastname: Flumian
authors.affiliation: Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo", Área Investigaciones, Av. San Martín 5481, Buenos Aires, Argentina.|CONICET, Buenos Aires, Argentina.
authors.forename: Elisa D
authors.initials: ED
authors.lastname: Bal de Kier Joffé
authors.affiliation: Laboratorio de Oncología Molecular, División de Productos Farmacéuticos, Centro de Genética Ingeniería y Biotecnología (CIGB), Havana, Cuba.
authors.forename: Silvio E
authors.initials: SE
authors.lastname: Perea
authors.affiliation: CONICET, Buenos Aires, Argentina.|Laboratorio de Oncología Molecular, Universidad Nacional de Quilmes, Bernal, Buenos Aires, Argentina.
authors.forename: Hernán G
authors.initials: HG
authors.lastname: Farina
authors.affiliation: Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo", Área Investigaciones, Av. San Martín 5481, Buenos Aires, Argentina.|CONICET, Buenos Aires, Argentina.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Todaro
authors.affiliation: Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo", Área Investigaciones, Av. San Martín 5481, Buenos Aires, Argentina.|CONICET, Buenos Aires, Argentina.
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Urtreger
keywords: CIGB-300; CK2; NF-κB; NSCLC