The MNK1/2-eIF4E Axis as a Potential Therapeutic Target in Melanoma

Abstract

Melanoma is a type of skin cancer that originates in the pigment-producing cells of the body known as melanocytes. Most genetic aberrations in melanoma result in hyperactivation of the mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. We and others have shown that a specific protein synthesis pathway known as the MNK1/2-eIF4E axis is often dysregulated in cancer. The MNK1/2-eIF4E axis is a point of convergence for these signaling pathways that are commonly constitutively activated in melanoma. In this review we consider the functional implications of aberrant mRNA translation in melanoma and other malignancies. Moreover, we discuss the consequences of inhibiting the MNK1/2-eIF4E axis on the tumor and tumor-associated cells, and we provide important avenues for the utilization of this treatment modality in combination with other targeted and immune-based therapies. The past decade has seen the increased development of selective inhibitors to block the action of the MNK1/2-eIF4E pathway, which are predicted to be an effective therapy regardless of the melanoma subtype (e.g., cutaneous, acral, and mucosal).

p38-MAPK mediated rRNA processing and translation regulation enables PrE differentiation during mouse blastocyst maturation

“…Although p38-MAPK activity has been reported to regulate protein synthesis in other contexts 46 , mTOR mediated translation regulation represents the most understood and extensively studied pathway, particularly in development 47 . Observations from studies of cancer biology indicate a possible convergence of both pathways towards positive regulation of eIF4E-sensitve cap-dependent mRNA translation 48,49 . Therefore, the generally significant role mTOR plays in translation regulation, coupled to a recent report describing blastocyst diapause caused by attenuated translation and transcription after mTOR inhibition 41 , prompted us to investigate our observed p38-MAPK phenotypes in conjunction with mTOR activity.…”

The pleiotropic effects of the MNK1/2-eIF4E axis support immune suppression and metastasis in a model of postpartum breast cancer

“…Such data indicate that fibroblast-derived IL-33 signals in a paracrine fashion to ST2-expressing breast cancer cells to augment tumor cell invasion. Therefore, we chose to further dissect how IL-33 signals downstream of ST2 in breast tumor cells, focusing on the p38 and ERK1/2 MAPK signaling proteins, which lie immediately upstream of MNK1/2 activation(41). Stimulation of 66cl4 cells with recombinant murine IL-33 (rIL-33) resulted in increased phosphorylation of both p38 MAPK and eIF4E, but not phosphorylation of ERK1/2 (Figure 3b, Supplementary 4b), and promoted 66cl4 (Figure 3c) and E0771 invasion (Supplementary Figure 4c).…”

Inhibition Effect of Chloroquine and Integrin-Linked Kinase Knockdown on Translation in Melanoma Cells

“…We observed a decreased expression of eIF4E as well as a decreased phosphorylation on S209 in all cases of treatment; however, in metastatic cell lines 1205Lu after CQ treatment, the decrease in phosphorylation is slight but accompanied by an amazingly low protein level. BRAF mutation in melanoma cells results in constitutive activation of the MEK/ERK pathway and activation of MNK1/2 [ 43 ]. A major mechanism for global translational control involves phosphorylation of the α subunit of eIF2 on S51, which represses the delivery of initiator methionyl-tRNA to the translational machinery [ 34 ].…”