The Prometastatic Ribosomal S6 Kinase 2-cAMP Response Element-binding Protein (RSK2-CREB) Signaling Pathway Up-regulates the Actin-binding Protein Fascin-1 to Promote Tumor Metastasis

Li, Dan; Jin, Lingtao; Alesi, Gina N.; Kim, Young Mee; Fan, Jun; Seo, Jae Ho; Wang, Dongsheng; Tucker, Meghan; Gu, Ting; Lee, Benjamin H.; Taunton, Jack; Magliocca, Kelly R.; Chen, Zhuo G.; Shin, Dong M.; Khuri, Fadlo R.; Kang, Sumin

doi:10.1074/jbc.m113.500561

Cited by 45 publications

(38 citation statements)

References 45 publications

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“…Kang et al (46) reported that silencing RSK2 decreased metastatic colonization to the lymph nodes using a human head and neck squamous cell carcinoma line. They further followed up on these observations using the RSK CTKD inhibitor, FMK-MEA, which resulted in a modest decrease in metastatic tumor burden from 97% to 79% (47). In a screen Lara et al (48) identified that loss of RSK1 increased motility in lung cancer lines but in contrast Zhou et al (49) found that inhibition of RSK activity was associated with decreased motility in lung cancer lines.…”

Section: Discussionmentioning

confidence: 99%

Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer

Ludwik

Campbell

et al. 2016

Molecular Cancer Therapeutics

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Metastatic breast cancer is an incurable disease and identification of novel therapeutic opportunities is vital. Triple negative breast cancer (TNBC) frequently metastasizes and high levels of activated RSK, a downstream MEK-ERK1/2 effector, are found in TNBC. We demonstrate using direct pharmacological and genetic inhibition of RSK1/2 that these kinases contribute to the TNBC metastatic process in vivo. Kinase profiling demonstrated that RSK1 and RSK2 are the predominant kinases targeted by the new inhibitor, which is based on the natural product, SL0101. Further evidence for selectivity was provided by the observations that silencing RSK1 and RSK2 eliminated the ability of the analogue to further inhibit survival or proliferation of a TNBC cell line. In vivo, the new derivative was as effective as the FDA-approved MEK inhibitor, trametinib, in reducing the establishment of metastatic foci. Importantly, inhibition of RSK1/2 did not result in activation of AKT, which is known to limit the efficacy of MEK inhibitors in the clinic. Our results demonstrate that RSK is a major contributor to the TNBC metastatic program and provide preclinical proof-of-concept for the efficacy of the novel SL0101 analogue in vivo.

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Section: Discussionmentioning

confidence: 99%

Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer

Ludwik

Campbell

et al. 2016

Molecular Cancer Therapeutics

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“…IHC analysis of GDH1 expression was performed according to the protocol described previously (Li et al, 2013). Approval of use of human specimens was given by the Institutional Review Board of Emory University.…”

Section: Methodsmentioning

confidence: 99%

Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth

et al. 2015

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SUMMARY How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) is commonly upregulated in human cancers. GDH1 is important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate (α-KG) and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a ROS scavenging enzyme glutathione peroxidase 1 (GPx1). Targeting GDH1 by shRNA or a small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth.

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“…In normal prenatal pig skeletal muscle, FSCN1 expression increases during major muscle developmental spurts, but postnatally it is expressed highly only in brain tissues during accelerated neural cell development [133] . The CREB pathway is often activated in different metastatic human cancers, causing the upregulation of FSCN1 expression [134] . In HNSCC patients, expression of RSK2 and FSCN1 proteins correlate closely.…”

Section: Cell Factors Deregulated In Cancer By Myomirsmentioning

confidence: 99%

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

Mitchelson¹

2015

WJBC

136

132

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MicroRNAs are small non-coding RNAs that participate in different biological processes, providing subtle combinational regulation of cellular pathways, often by regulating components of signalling pathways. Aberrant expression of miRNAs is an important factor in the development and progression of disease. The canonical myomiRs (miR-1, -133 and -206) are central to the development and health of mammalian skeletal and cardiac muscles, but new findings show they have regulatory roles in the development of other mammalian non-muscle tissues, including nerve, brain structures, adipose and some specialised immunological cells. Moreover, the deregulation of myomiR expression is associated with a variety of different cancers, where typically they have tumor suppressor functions, although examples of an oncogenic role illustrate their diverse function in different cell environments. This review examines the involvement of the related myomiRs at the crossroads between cell development/ tissue regeneration/tissue inflammation responses, and cancer development. Core tip: The roles of the canonical muscle-associated microRNAs are reviewed, including microRNA families miR-1 and miR-133, and single miR-206, which are collectively known as the "myomiRs". The myomiRs act at the crossroads of the molecular regulation of muscle cells, linking between pathways for cell differentiation, development and maintenance, but also potentiate aberrant cell growth in numerous non-muscle cancers. Typically myomiRs are downregulated in cancers, but some myomiRs are upregulated in a few cancers, yet each dysregulation event advances tumor progression. The review examines normal and disease-linked molecular changes associated with the myomiRs, and collates the extensive literature into accessible tables. REVIEW

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The Prometastatic Ribosomal S6 Kinase 2-cAMP Response Element-binding Protein (RSK2-CREB) Signaling Pathway Up-regulates the Actin-binding Protein Fascin-1 to Promote Tumor Metastasis

Cited by 45 publications

References 45 publications

Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer

Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer

Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

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