TY - JOUR
T1 - Anti-invasive and antimetastatic activities of ribosomal protein S6 kinase 4 in breast cancer cells
AU - Thakur, Archana
AU - Sun, Yuan
AU - Bollig, Aliccia
AU - Wu, Jack
AU - Biliran, Hector
AU - Banerjee, Sanjeev
AU - Sarkar, Fazlul H.
AU - Liao, D. Joshua
PY - 2008/7/15
Y1 - 2008/7/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-08-0458
DO - 10.1158/1078-0432.CCR-08-0458
M3 - Article
C2 - 18628456
AN - SCOPUS:51649086495
SN - 1078-0432
VL - 14
SP - 4427
EP - 4436
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -