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 sur… Show more
“…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).…”
SUMMARYCancer is driven by genetic and epigenetic alterations that allow cells to overproliferate and escape mechanisms that normally control their survival and migration. Many of these alterations map to signaling pathways that control cell growth and division, cell death, cell fate, and cell motility, and can be placed in the context of distortions of wider signaling networks that fuel cancer progression, such as changes in the tumor microenvironment, angiogenesis, and inflammation. Mutations that convert cellular proto-oncogenes to oncogenes can cause hyperactivation of these signaling pathways, whereas inactivation of tumor suppressors eliminates critical negative regulators of signaling. An examination of the PI3K-Akt and Ras-ERK pathways illustrates how such alterations dysregulate signaling in cancer and produce many of the characteristic features of tumor cells.
“…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).…”
SUMMARYCancer is driven by genetic and epigenetic alterations that allow cells to overproliferate and escape mechanisms that normally control their survival and migration. Many of these alterations map to signaling pathways that control cell growth and division, cell death, cell fate, and cell motility, and can be placed in the context of distortions of wider signaling networks that fuel cancer progression, such as changes in the tumor microenvironment, angiogenesis, and inflammation. Mutations that convert cellular proto-oncogenes to oncogenes can cause hyperactivation of these signaling pathways, whereas inactivation of tumor suppressors eliminates critical negative regulators of signaling. An examination of the PI3K-Akt and Ras-ERK pathways illustrates how such alterations dysregulate signaling in cancer and produce many of the characteristic features of tumor cells.
“…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).…”
Y-box binding protein 1 (YB-1) is an imperative biomarker for the clinical outcome of cancer patients. An overexpression of YB-1 in cancerous and adjoining tissues is an indication of aggressiveness and advanced stages. In normal resting cells, YB-1 is localized in cytoplasm while in stress conditions like cancer, nuclear shuttling of YB-1 takes place. In this review, the clinical importance of YB-1 in different cancers and the mechanism behind YB-1 nuclear shuttling have been discussed in detail. Targeted chemotherapies or molecularly targeted drugs of great importance can target and block specific molecules implicated in tumor growth and progression. YB-1 has been considered as a bonafide oncogene and accumulating evidences show the therapeutic importance of YB-1. Therapeutic strategies targeting YB-1 may improve the survival rate in cancer patients. This review extensively discusses the therapeutic importance of YB-1.
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Mini-reviewThis article was downloaded by you on: Apr 30, 2016 In normal resting cells, full length YB-1 is mainly present in the cytoplasm of cells under stress during pathological conditions including inflammation, oxidative stress and cancer conditions. Particular segment of the YB-1 flips to the nucleus (Koike et al., 1997;Higashi et al., 2011).In this review, with the nuclear shuttling, clinical significance of YB-1 in cancer and as a therapeutic target have been evaluated from the existing literature. The present literature analysis shows the prospective role of YB-1 in cancer progression and drug resistance which could be harnessed to make it a promising therapeutic target.
Nuclear shuttling of YB-1Since a number of functions have been assigned to YB-1, therefore, the sub-cellular protein shuttling needs to be highly stringent. In general, specific nuclear export signals and nuclear localization signals (NLS) contribute and direct the multifunctional shuttling and tasking (Bader and Vogt, 2005). Literature suggests three nuclear localization signals in YB-1 i.e. NLS1 (aa149-55), NLS2 (aa185-94) and NLS3 (276-92) (van Roeyen et al., 2013). The NLS3 is bipartite in composition and both the parts are essential for functionality. Irrespective of this, the changes of the spatial organization of 2 parts doesn't affect nuclear shuttling. Both NLS2 and NLS3 are essential for functionality and contain tyrosine residues which are required for phosphorylation. The full length YB-1 phosphorylated at tyrosine 281 in NLS3 has been found to be localized in the nucleus while the unphosphorylated YB-1 localized in the cytoplasm. This indicates that the phosphorylation at T-281 renders complete YB-1 to be localized in nucleus under normal conditions (van Roeyen et al., 2013). At the time of stress or cell stimulation, nuclear flipping of shortened YB-1 having N-terminal portion of the proteins takes place through a highly regulated process (Bader and Vogt, 2005;van Roeyen et al., 2013). Jürchott et al. (2003) suggested that the both C-terminal and cold shock domain of YB...
“…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].…”
Section: Erk Isoforms and Regulation Erk1/2 Phosphorylationmentioning
Taking in account the inspiring outcomes of ERK inhibitors in preclinical research, ERK1/2 might be the optimal target to overcome acquired drug resistance in RAF-MEK-ERK pathway.
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