The synthetic peptide CIGB-300 modulates CK2-dependent signaling pathways affecting the survival and chemoresistance of non-small cell lung cancer cell lines
| Autor: | Laura B. Todaro, Silvio E. Perea, Damian E. Berardi, Hernán G. Farina, Carolina Flumian, Alejandro J. Urtreger, Stefano M. Cirigliano, Elisa Bal de Kier Joffé, María I. Díaz Bessone |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Oncology Cancer Research medicine.medical_specialty CIENCIAS MÉDICAS Y DE LA SALUD CK2 Inmunología NSCLC lcsh:RC254-282 NF-κB 03 medical and health sciences 0302 clinical medicine Internal medicine CIGB-300 Genetics Medicine Viability assay lcsh:QH573-671 Lung cancer A549 cell Cisplatin lcsh:Cytology business.industry Kinase Cancer purl.org/becyt/ford/3.1 [https] lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease NF-ΚB Medicina Básica 030104 developmental biology Apoptosis 030220 oncology & carcinogenesis Cancer research purl.org/becyt/ford/3 [https] Signal transduction Primary Research business medicine.drug |
| Zdroj: | Cancer Cell International, Vol 17, Iss 1, Pp 1-16 (2017) Cancer Cell International CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| ISSN: | 1475-2867 |
| DOI: | 10.1186/s12935-017-0413-y |
| Popis: | 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 the effects of CIGB-300 treatment targeting CK2-dependent signaling pathways in NSCLC cell lines and 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. Fil: Cirigliano, Stéfano Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Díaz Bessone, María Inés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Berardi, Damian Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Flumian, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Bal, Elisa Dora. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Perea, Silvio E.. Centro de Genética Ingeniería y Biotecnología; Cuba Fil: Farina, Hernán Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina Fil: Todaro, Laura Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Urtreger, Alejandro Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina |
| Databáze: | OpenAIRE |
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