Targeted elimination of senescent Ras-transformed cells by suppression of MEK/ERK pathway
| Autor: | O. A. Bystrova, Valery A. Pospelov, M. G. Martynova, Tatiana V. Pospelova, Elena Y. Kochetkova, G. I. Blinova |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway autophagy Aging Programmed cell death senescence Lung Neoplasms Time Factors Cell Survival Population Adenocarcinoma of Lung Apoptosis AMP-Activated Protein Kinases Adenocarcinoma medicine.disease_cause Proto-Oncogene Proteins p21(ras) 03 medical and health sciences chemistry.chemical_compound Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Extracellular Signal-Regulated MAP Kinases education Protein Kinase Inhibitors Cellular Senescence education.field_of_study Kinase Autophagy Sodium butyrate Cell Biology Fibroblasts MAP Kinase Kinase Kinases Mitochondria Rats Cell biology Histone Deacetylase Inhibitors 030104 developmental biology chemistry A549 Cells Drug Resistance Neoplasm Carcinogenesis MEK/ERK Research Paper Signal Transduction |
| Zdroj: | Aging (Albany NY) |
| ISSN: | 1945-4589 |
| DOI: | 10.18632/aging.101325 |
| Popis: | The Ras-Raf-MEK-ERK pathway plays a central role in tumorigenesis and is a target for anticancer therapy. The successful strategy based on the activation of cell death in Ras-expressing cells is associated with the suppression of kinases involved in Ras pathway. However, activation of cytoprotective autophagy overcomes antiproliferative effect of the inhibitors and develops drug resistance. We studied whether cellular senescence induced by HDAC inhibitor sodium butyrate in E1a+cHa-Ras-transformed rat embryo fibroblasts (ERas) and A549 human Ki-Ras mutated lung adenocarcinoma cells would enhance the tumor suppressor effect of MEK/ERK inhibition. Treatment of control ERas cells with PD0325901 for 24 h results in mitochondria damage and apoptotic death of a part of cellular population. However, the activation of AMPK-dependent autophagy overcomes pro-apoptotic effects of MEK/ERK inhibitor and results in restoration of the mitochondria and rescue of viability. Senescent ERas cells do not develop cytoprotective autophagy upon inhibition of MEK/ERK pathway due to spatial dissociation of lysosomes and autophagosomes in the senescent cells. Senescent cells are unable to form the autophagolysosomes and to remove the damaged mitochondria resulting in apoptotic death. Our data show that suppression of MEK/ERK pathway in senescent cells provides a new strategy for elimination of Ras-expressing cells. |
| Databáze: | OpenAIRE |
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