Anti-invasive and Antimetastatic Activities of Ribosomal Protein S6 Kinase 4 in Breast Cancer Cells

• Published in: Clinical cancer research 2008-07, Vol.14 (14), p.4427-4436
• Main Authors: Thakur, Archana, Sun, Yuan, Bollig, Aliccia, Wu, Jack, Biliran, Hector, Banerjee, Sanjeev, Sarkar, Fazlul H, Liao, D Joshua
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; breast cancer; Breast Neoplasms - enzymology; Breast Neoplasms - pathology; c-Myc; Cell Line, Tumor; Cell Movement - physiology; Cell Proliferation; chemotaxis; Claudins; Female; Gene Expression Regulation, Neoplastic - physiology; Humans; Immunohistochemistry; invasion; Membrane Proteins - biosynthesis; metastasis; Mice; Mice, SCID; Neoplasm Invasiveness; Receptors, CXCR4 - biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; RSK4
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-0458

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 G 0 -G 1 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 down-regulation 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.