RSK Isoforms in Cancer Cell Invasion and Metastasis

Abstract

Metastasis, the spreading of cancer cells from a primary tumor to secondary sites throughout the body, is the primary cause of death for cancer patients. New therapies that prevent invasion and metastasis in combination with current treatments could therefore significantly reduce cancer recurrence and morbidity. Metastasis is driven by altered signaling pathways that induce changes in cell-cell adhesion, the cytoskeleton, integrin function, protease expression, epithelial to mesenchymal transition and cell survival. The RSK family of kinases is a group of ERK/MAPK effectors that can regulate these steps of metastasis by phosphorylating both nuclear and cytoplasmic targets. However, our understanding of RSK function in metastasis remains incomplete and is complicated by the fact that the four RSK isoforms perform non-redundant, sometimes opposing functions. While some isoforms promote cell motility and invasion by altering transcription and integrin activity, others impair cell motility and invasion through effects on the actin cytoskeleton. The mechanism of RSK action depends both on the isoform and the cancer type. However, despite the variance in RSK-mediated outcomes, chemical inhibition of this group of kinases has proven effective in blocking invasion and metastasis of several solid tumors in pre-clinical models. RSKs are therefore a promising drug target for anti-metastatic cancer treatments that could supplement and improve current therapeutic approaches. This review highlights contradiction and agreement in the current data on the function of RSK isoforms in metastasis and suggests ways forward in developing RSK inhibitors as new anti-metastasis drugs.

Signal Transduction in Cancer

“…For example, Akt1 specifically suppresses migration in many contexts through inhibition of ERK, the transcription factor NFAT, TSC2, or phosphopalladin-induced actin bundling, whereas Akt2 promotes migration through regulation of integrin expression and effects on the epithelial-mesenchymal transition (EMT) (see below; Chin and Toker 2011). Similarly, some isoforms of ERK target RSK to promote cell motility and invasion by altering transcription and integrin activity, whereas others impair cell motility and invasion through effects on the actin cytoskeleton (Sulzmaier and Ramos 2013).…”

Nuclear shuttling of Y Box binding protein-1, its clinical relevance in cancer and as a therapeutic target

“…YB-1 has been found to be overexpressed in human prostate cancer tissues during tumor progression, and even after androgen ablation in a mouse xenograft model . Ribosomal S6 kinase family (RSK1, RSK2, RSK3 and RSK4) proteins hinder apoptosis by defending mitochondrial veracity and regulate proliferation as well as patient survival in many human cancers at elevated levels (Stratford et al, 2008;Sulzmaier and Ramos, 2013).…”

The RAF-MEK-ERK Pathway: Targeting ERK to Overcome Obstacles of Effective Cancer Therapy

“…DFG motif is essential for enzyme catalysis and phosphotransfer [114]. Then the signal is transmitted to C-terminal lobe and phosphory lates the substrate protein, such as RSK [115], cytosolic phospholipase A2, microtubule-associated proteins and a variety of scaffold proteins [116].…”