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

Abstract

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 hresults 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.

Identification of a Proteomic Signature of Senescence in Primary Human Mammary Epithelial Cells

“…Here, based on our proteomic signature of senescence, we predicted that EGFR inhibitors (e.g., dacomitinib, AZD8931), MEK inhibitors, and dasatinib are senolytic agents for HMECs. Interestingly, MEK inhibitors have been shown to eliminate senescent Ras-expressing cells (Kochetkova et al 2017). Moreover, in IMR90 and HUVECs, the cytokine-mediated induction of senescence can be blocked by pharmacological inhibition or genetic knockdown of EGFR (Shang et al 2020).…”

Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors

“…These neural aggregates lead to behavior impairments that can be resolved with the maintenance of autophagy pathways in neurons (99). In addition, autophagy is involved in a number of degenerative disorders such as cognitive decline (14, 56, 100), AD (40, 48, 83, 101, 102), Parkinson’s disease (11, 87, 98, 103), Huntington’s disease (59, 104, 105), DM (14, 17, 40, 89, 106, 107), and aging processes (8, 40, 85, 91, 108–111). Autophagy also may be required to preserve metabolic homeostasis with mTOR (112).…”

Maintaining the stemness of satellite cells during long-term culture

“…The ERK signal in replicative senescence by long-term passaging has been well studied. ERK signal is decreased during long-term passage 105,106 . The suppression of MEK/ ERK pathway in senescent cells leads to accumulation of damaged mitochondria and reactive oxygen species (ROS) 105 .…”

“…ERK signal is decreased during long-term passage 105,106 . The suppression of MEK/ ERK pathway in senescent cells leads to accumulation of damaged mitochondria and reactive oxygen species (ROS) 105 . Dephosphorylation of ERK1/2 leads to p53mediated upregulation of MKP-3, which contributes to the senescent phenotype 107 .…”

“…Further maintenance of satellite cell stemness can depend on cell signaling during proliferation. p38, a subgroup of the Mitogen-activated protein kinase (MAPKs), that can be activated by stress signals, inflammatory cytokines, and many other stimuli has been implicated in cell proliferation, senescence, apoptosis and other cellular processes 105,106 . The p38α/β MAPK signaling pathway regulates asymmetric division of satellite cells 107 .…”