Anti-invasive and antimetastatic activities of ribosomal protein S6 kinase 4 in breast cancer cells

Archana Thakur, Yuan Sun, Aliccia Bollig, Jack Wu, Hector Biliran, Sanjeev Banerjee, Fazlul H. Sarkar, D. Joshua Liao

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47 Scopus citations

Abstract

Purpose: We have previously shown that p90 ribosomal protein S6 kinase 4 (RSK4), an X-linked gene, is highly up-regulated in mammary tumors of MMTV-c-Myc transgenic mice. In this study, we further investigated whether RSK4 inhibits or promotes breast tumor growth and progression. Experimental Design: Stable overexpression or small interfering RNA-mediated knockdown of RSK4 was done in the MDA-MB-231 cell line. Stable clones were tested for cell proliferation, anchorage-independent growth in soft agar, invasive and metastatic ability of these clones in vitro and tumorigenesis, invasive and metastatic ability in vivo in severe combined immunodeficient mice. Results: Here, we show that exogenous expression of RSK4 resulted in decreased cell proliferation and increased accumulation of cells in Go-G1 phase, which paralleled with enhanced expression of tumor suppressor genes: retinoblastoma protein, retinobl astoma-associated 46 kDa protein, and p21 protein. Overexpression of RSK4 resulted in reduced colony formation in soft agar and suppressed invasive and migratory activities of MDA-MB-231 cells both in vitro and in vivo. Importantly, RSK4-overexpressing cells showed up-regulation of claudin-2 and downregulation of CXCR4, both of these play roles in invasion and chemotaxis. Conclusions: These results indicate that RSK4 expression may limit the oncogenic, invasive, and metastatic potential of breast cancer cells. Anti-invasive and antimetastatic activities of RSK4 may be, in part, due to its regulation of claudin-2. Increased expression of RSK4 in c-Myc-overexpressing cells and a dose-dependent induction of luciferase reporter gene activity suggest that c-Myc may regulate RSK4 expression.

Original languageEnglish (US)
Pages (from-to)4427-4436
Number of pages10
JournalClinical Cancer Research
Volume14
Issue number14
DOIs
StatePublished - Jul 15 2008

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    Thakur, A., Sun, Y., Bollig, A., Wu, J., Biliran, H., Banerjee, S., Sarkar, F. H., & Liao, D. J. (2008). Anti-invasive and antimetastatic activities of ribosomal protein S6 kinase 4 in breast cancer cells. Clinical Cancer Research, 14(14), 4427-4436. https://doi.org/10.1158/1078-0432.CCR-08-0458