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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.
J Biol Chem. 2013 Nov 08; 288(45):32528-38.JB

Abstract

Metastasis is the leading cause of death in patients with breast, lung, and head and neck cancers. However, the molecular mechanisms underlying metastases in these cancers remain unclear. We found that the p90 ribosomal S6 kinase 2 (RSK2)-cAMP response element-binding protein (CREB) pathway is commonly activated in diverse metastatic human cancer cells, leading to up-regulation of a CREB transcription target Fascin-1. We also observed that the protein expression patterns of RSK2 and Fascin-1 correlate in primary human tumor tissue samples from head and neck squamous cell carcinoma patients. Moreover, knockdown of RSK2 disrupts filopodia formation and bundling in highly invasive cancer cells, leading to attenuated cancer cell invasion in vitro and tumor metastasis in vivo, whereas expression of Fascin-1 significantly rescues these phenotypes. Furthermore, targeting RSK2 with the small molecule RSK inhibitor FMK-MEA effectively attenuated the invasive and metastatic potential of cancer cells in vitro and in vivo, respectively. Taken together, our findings for the first time link RSK2-CREB signaling to filopodia formation and bundling through the up-regulation of Fascin-1, providing a proinvasive and prometastatic advantage to human cancers. Therefore, protein effectors of the RSK2-CREB-Fascin-1 pathway represent promising biomarkers and therapeutic targets in the clinical prognosis and treatment of metastatic human cancers.

Authors+Show Affiliations

From the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24085294

Citation

Li, Dan, et al. "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." The Journal of Biological Chemistry, vol. 288, no. 45, 2013, pp. 32528-38.
Li D, Jin L, Alesi GN, et al. 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. J Biol Chem. 2013;288(45):32528-38.
Li, D., Jin, L., Alesi, G. N., Kim, Y. M., Fan, J., Seo, J. H., Wang, D., Tucker, M., Gu, T. L., Lee, B. H., Taunton, J., Magliocca, K. R., Chen, Z. G., Shin, D. M., Khuri, F. R., & Kang, S. (2013). 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. The Journal of Biological Chemistry, 288(45), 32528-38. https://doi.org/10.1074/jbc.M113.500561
Li D, et al. 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. J Biol Chem. 2013 Nov 8;288(45):32528-38. PubMed PMID: 24085294.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Li,Dan, AU - Jin,Lingtao, AU - Alesi,Gina N, AU - Kim,Young-Mee, AU - Fan,Jun, AU - Seo,Jae Ho, AU - Wang,Dongsheng, AU - Tucker,Meghan, AU - Gu,Ting-Lei, AU - Lee,Benjamin H, AU - Taunton,Jack, AU - Magliocca,Kelly R, AU - Chen,Zhuo G, AU - Shin,Dong M, AU - Khuri,Fadlo R, AU - Kang,Sumin, Y1 - 2013/10/01/ PY - 2013/10/3/entrez PY - 2013/10/3/pubmed PY - 2014/1/21/medline KW - Cell Invasion KW - Cell Migration KW - Fascin-1 KW - Filopodia KW - Metastasis KW - Ribosomal S6 Kinase 2 KW - Serine Threonine Protein Kinase KW - Signal Transduction KW - cAMP Response Element-binding SP - 32528 EP - 38 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 288 IS - 45 N2 - Metastasis is the leading cause of death in patients with breast, lung, and head and neck cancers. However, the molecular mechanisms underlying metastases in these cancers remain unclear. We found that the p90 ribosomal S6 kinase 2 (RSK2)-cAMP response element-binding protein (CREB) pathway is commonly activated in diverse metastatic human cancer cells, leading to up-regulation of a CREB transcription target Fascin-1. We also observed that the protein expression patterns of RSK2 and Fascin-1 correlate in primary human tumor tissue samples from head and neck squamous cell carcinoma patients. Moreover, knockdown of RSK2 disrupts filopodia formation and bundling in highly invasive cancer cells, leading to attenuated cancer cell invasion in vitro and tumor metastasis in vivo, whereas expression of Fascin-1 significantly rescues these phenotypes. Furthermore, targeting RSK2 with the small molecule RSK inhibitor FMK-MEA effectively attenuated the invasive and metastatic potential of cancer cells in vitro and in vivo, respectively. Taken together, our findings for the first time link RSK2-CREB signaling to filopodia formation and bundling through the up-regulation of Fascin-1, providing a proinvasive and prometastatic advantage to human cancers. Therefore, protein effectors of the RSK2-CREB-Fascin-1 pathway represent promising biomarkers and therapeutic targets in the clinical prognosis and treatment of metastatic human cancers. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/24085294/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_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=24085294 DB - PRIME DP - Unbound Medicine ER -