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

Abstract

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.

Niclosamide Suppresses Migration and Invasion of Human Osteosarcoma Cells by Repressing TGFBI Expression via the ERK Signaling Pathway

“…The ERK signaling is a pathway related to other different signaling cascades and, therefore, to various biological processes in various cancers [ 31 , 32 , 33 ]. In osteosarcoma, Chen et al, reported that c-Met Inhibitor suppresses osteosarcoma progression via the ERK1/2 pathway [ 34 ].…”

ACAGT-007a, an ERK MAPK Signaling Modulator, in Combination with AKT Signaling Inhibition Induces Apoptosis in KRAS Mutant Pancreatic Cancer T3M4 and MIA-Pa-Ca-2 Cells

“…Notably, in T3M4 cells harboring the KRAS Q61H mutation, ERK activation stimulated by GT-7 is required for apoptosis induction, as evidenced by the significant cancellation of apoptosis induction by the MEK inhibitor U0126. A growing number of the literature showed that more than 50 compounds have been reported to induce ERK-dependent cell death in various tumor cell types [ 8 , 9 ]. However, thus far, no reports have been made on an anti-cancer compound capable of inducing ERK-dependent apoptosis.…”

“…ACA-28 and its lead derivative ACAGT-007a (GT-7; described as 2b in the previous reports) selectively induce apoptosis in several ERK-active melanoma cell lines, including SK-MEL-28, expressing the oncogenic mutant BRAF (V600E), by further stimulating ERK phosphorylation levels [ 7 ]. Notably, recent studies have highlighted the pro-apoptotic functions of ERK1/2 kinases and various compounds, including betulinic acid, piperlongumine, and cisplatin, trigger cancer cell death by enhancing ERK1/2 signaling [ 8 , 9 ]. Although the list of the compounds which mediate ERK activation and apoptosis is expanding, the ERK-dependent apoptosis in pancreatic cancer by an anti-cancer compound has never been reported.…”

Novel Mechanism by a Bis-Pyridinium Fullerene Derivative to Induce Apoptosis by Enhancing the MEK-ERK Pathway in a Reactive Oxygen Species-Independent Manner in BCR-ABL-Positive Chronic Myeloid Leukemia-Derived K562 Cells

“…There is another possibility that BPF could activate Raf-MEK-ERK pathway through inhibiting its specific protein phosphatases. Until now, only the DUSP family is well known as a specific protein phosphatase for MAP kinases; however, other types of protein phosphatases for Raf and MEK kinases have not been identified yet [ 33 ]. We would like to clarify the detailed mechanism for BPF-caused ERK activation in future project.…”