ERK: A Double-Edged Sword in Cancer. ERK-Dependent Apoptosis as a Potential Therapeutic Strategy for Cancer

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 10; p. 2509
• Main Authors: Sugiura, Reiko, Satoh, Ryosuke, Takasaki, Teruaki
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22-09-2021; MDPI
• Subjects: ACA-28; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Cancer; cancer treatment; Cell cycle; Cell death; Cell differentiation; Cell growth; Cell proliferation; Cytokines; Cytoplasm; Dual-Specificity Phosphatases - metabolism; DUSP/MKP; Extracellular signal-regulated kinase; Feedback; Gene expression; Growth factors; Humans; Kinases; Localization; MAP Kinase Signaling System - drug effects; Melanoma; Metabolic pathways; Mutation; Neoplasms - drug therapy; Neoplasms - metabolism; Phosphatase; Phosphorylation; Physiology; Protein Kinase Inhibitors - pharmacology; Proteins; Raf protein; RAS/RAF/MEK/ERK signaling; Review; Signal transduction; Signal Transduction - drug effects; Transcription factors; Tumorigenesis; Tumors; DUSP/MKP; cancer treatment; apoptosis; RAS/RAF/MEK/ERK signaling; ACA-28
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10102509

The RAF/MEK/ERK signaling pathway regulates diverse cellular processes as exemplified by cell proliferation, differentiation, motility, and survival. Activation of ERK1/2 generally promotes cell proliferation, and its deregulated activity is a hallmark of many cancers. Therefore, components and regulators of the ERK pathway are considered potential therapeutic targets for cancer, and inhibitors of this pathway, including some MEK and BRAF inhibitors, are already being used in the clinic. Notably, ERK1/2 kinases also have pro-apoptotic functions under certain conditions and enhanced ERK1/2 signaling can cause tumor cell death. Although the repertoire of the compounds which mediate ERK activation and apoptosis is expanding, and various anti-cancer compounds induce ERK activation while exerting their anti-proliferative effects, the mechanisms underlying ERK1/2-mediated cell death are still vague. Recent studies highlight the importance of dual-specificity phosphatases (DUSPs) in determining the pro- versus anti-apoptotic function of ERK in cancer. In this review, we will summarize the recent major findings in understanding the role of ERK in apoptosis, focusing on the major compounds mediating ERK-dependent apoptosis. Studies that further define the molecular targets of these compounds relevant to cell death will be essential to harnessing these compounds for developing effective cancer treatments.