Targeted elimination of senescent Ras-transformed cells by suppression of MEK/ERK pathway

• Published in: Aging (Albany, NY.) Vol. 9; no. 11; pp. 2352 - 2375
• Main Authors: Kochetkova, Elena Y, Blinova, Galina I, Bystrova, Olga A, Martynova, Marina G, Pospelov, Valery A, Pospelova, Tatiana V
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 14-11-2017
• Subjects: A549 Cells; Adenocarcinoma - drug therapy; Adenocarcinoma - enzymology; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adenocarcinoma of Lung; AMP-Activated Protein Kinases - metabolism; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Autophagy - drug effects; Cell Survival - drug effects; Cellular Senescence - drug effects; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Fibroblasts - drug effects; Fibroblasts - enzymology; Fibroblasts - pathology; Histone Deacetylase Inhibitors - pharmacology; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - pathology; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - metabolism; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Rats; Research Paper; Signal Transduction - drug effects; Time Factors; senescence; apoptosis; autophagy; mitochondria; MEK/ERK
• ISSN: 1945-4589; 1945-4589
• DOI: 10.18632/aging.101325

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
-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.