Autophagic cell death associated to Sorafenib in renal cell carcinoma is mediated through Akt inhibition in an ERK1/2 independent fashion

Autor: María José Ruiz-Hidalgo, Antonio S. Salinas, Marta Ortega-Muelas, Ricardo Sánchez-Prieto, José M. Giménez-Bachs, Raquel Pascual-Serra, Francisco J. Cimas, Maria Ll. Valero, Diego M. Fernández-Aroca, Olga Roche, Borja Belandia, Jesús García-Cano, Leticia Serrano-Oviedo
Přispěvatelé: Fundación Leticia Castillejo, Ministerio de Economía y Competitividad (España), European Commission
Rok vydání: 2018
Předmět:
0301 basic medicine
Cell signaling
Protein Extraction
lcsh:Medicine
Signal transduction
urologic and male genital diseases
p38 Mitogen-Activated Protein Kinases
Biochemistry
0302 clinical medicine
Medicine and Health Sciences
Enzyme assays
Colorimetric assays
lcsh:Science
Bioassays and physiological analysis
Cell Analysis
Caspase 7
Mitogen-Activated Protein Kinase 1
Extraction Techniques
Multidisciplinary
Mitogen-Activated Protein Kinase 3
MTT assay
biology
Cell Death
Kinase
Chemistry
Caspase 3
Signaling cascades
Sorafenib
Kidney Neoplasms
Oncology
Cell Processes
030220 oncology & carcinogenesis
Mitogen-activated protein kinase
medicine.drug
Research Article
Programmed cell death
Cell Viability Testing
MAPK signaling cascades
Signal Inhibition
Cell Survival
Autophagic Cell Death
ATG5
Blotting
Western
Carcinomas
03 medical and health sciences
Tubulins
Cell Line
Tumor
medicine
Autophagy
Humans
Kinase activity
Protein kinase B
Carcinoma
Renal Cell
PI3K/AKT/mTOR pathway
Mitogen-Activated Protein Kinase 7
lcsh:R
Renal Cell Carcinoma
Biology and Life Sciences
Cancers and Neoplasms
Proteins
Cell Biology
Research and analysis methods
Genitourinary Tract Tumors
Cytoskeletal Proteins
030104 developmental biology
Biochemical analysis
Cancer research
biology.protein
lcsh:Q
Proto-Oncogene Proteins c-akt
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
PLoS ONE, Vol 13, Iss 7, p e0200878 (2018)
PLoS ONE
ISSN: 2012-3086
Popis: [Objectives]: To fully clarify the role of Mitogen Activated Protein Kinase in the therapeutic response to Sorafenib in Renal Cell Carcinoma as well as the cell death mechanism associated to this kinase inhibitor, we have evaluated the implication of several Mitogen Activated Protein Kinases in Renal Cell Carcinoma-derived cell lines.
[Materials and methods]: An experimental model of Renal Cell Carcinoma-derived cell lines (ACHN and 786-O cells) was evaluated in terms of viability by MTT assay, induction of apoptosis by caspase 3/7 activity, autophagy induction by LC3 lipidation, and p62 degradation and kinase activity using phospho-targeted antibodies. Knock down of ATG5 and ERK5 was performed using lentiviral vector coding specific shRNA.
[Results]: Our data discard Extracellular Regulated Kinase 1/2 and 5 as well as p38 Mitogen Activated Protein Kinase pathways as mediators of Sorafenib toxic effect but instead indicate that the inhibitory effect is exerted through the PI3K/Akt signalling pathway. Furthermore, we demonstrate that inhibition of Akt mediates cell death associated to Sorafenib without caspase activation, and this is consistent with the induction of autophagy, as indicated by the use of pharmacological and genetic approaches.
[Conclusion]: The present report demonstrates that Sorafenib exerts its toxic effect through the induction of autophagy in an Akt-dependent fashion without the implication of Mitogen Activated Protein Kinase. Therefore, our data discard the use of inhibitors of the RAF-MEK-ERK1/2 signalling pathway in RCC and support the use of pro-autophagic compounds, opening new therapeutic opportunities for Renal Cell Carcinoma.
This work was supported by grants from Fundacion Leticia Castillejo Castillo, Ministerio de Economía y Competitividad (SAF2012-30862, SAF2015-64215R) to RSP and MJRH. RSP and MJRH Research Institutes, and the work carried out in their laboratories received support from the European Community through the Regional Development Funding Program (FEDER). OR has a contract for accessing the Spanish System of Science, Technology and Innovation (SECTI) funded by the University of Castilla La Mancha (UCLM).
Databáze: OpenAIRE
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