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p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cells
Sumin Kang, … , Dong M. Shin, Jing Chen
Sumin Kang, … , Dong M. Shin, Jing Chen
Published March 15, 2010
Citation Information: J Clin Invest. 2010;120(4):1165-1177. https://doi.org/10.1172/JCI40582.
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Research Article Oncology Article has an altmetric score of 3

p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cells

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Abstract

Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer and frequently metastasizes to LNs. Identifying metastasis-promoting factors is of immense clinical interest, as the prognosis for patients with even a single unilateral LN metastasis is extremely poor. Here, we report that p90 ribosomal S6 kinase 2 (RSK2) promotes human HNSCC cell invasion and metastasis. We determined that RSK2 was overexpressed and activated in highly invasive HNSCC cell lines compared with poorly invasive cell lines. Expression of RSK2 also correlated with metastatic progression in patients with HNSCC. Ectopic expression of RSK2 substantially enhanced the invasive capacity of HNSCC cells, while inhibition of RSK2 activity led to marked attenuation of invasion in vitro. Additionally, shRNA knockdown of RSK2 substantially reduced the invasive and metastatic potential of HNSCC cells in vitro and in vivo in a xenograft mouse model, respectively. Mechanistically, we determined that cAMP-responsive element-binding protein (CREB) and Hsp27 are phosphorylated and activated by RSK2 and are important for the RSK2-mediated invasive ability of HNSCC cells. Our findings suggest that RSK2 is involved in the prometastatic programming of HNSCC cells, through phosphorylation of proteins in a putative signaling network. Moreover, targeting RSK2 markedly attenuates in vitro invasion and in vivo metastasis of HNSCC cells, suggesting that RSK2 may represent a therapeutic target in the treatment of metastatic HNSCC.

Authors

Sumin Kang, Shannon Elf, Katherine Lythgoe, Taro Hitosugi, Jack Taunton, Wei Zhou, Li Xiong, Dongsheng Wang, Susan Muller, Songqing Fan, Shi-Yong Sun, Adam I. Marcus, Ting-Lei Gu, Roberto D. Polakiewicz, Zhuo (Georgia) Chen, Fadlo R. Khuri, Dong M. Shin, Jing Chen

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Figure 5

Targeting RSK2 by shRNA leads to decreased phosphorylation levels of multiple prometastatic protein factors, including tyrosine kinases, c-MET and FAK, and RSK2 phosphorylation substrates, CREB and Hsp27.

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Targeting RSK2 by shRNA leads to decreased phosphorylation levels of mul...
(A) Stable knockdown of RSK2 did not affect phosphorylation and activation levels of ERK, AKT, and STAT3. Immunoblotting was performed using cell lysates obtained from M4e-pLKO.1 or M4e-pLKO.1-RSK2 shRNA cells. (B) Immunoblotting results demonstrate that targeted downregulation of RSK2 resulted in decreased tyrosine phosphorylation and activation of prometastatic tyrosine kinases c-MET in M4e cells and FAK in 212LN and 37B cells. β-actin was detected as a loading control. (C) RSK2 directly phosphorylated Hsp27 at S78 and S82 but not S15. Purified rHsp27 WT and individual S15A, S78A, or S82A mutant proteins were incubated with active rRSK2 in an in vitro kinase assay. Phosphorylation at Ser15, Ser78, and Ser82 in rHsp27 was detected by specific antibodies phospho-Hsp27 pS15, pS78, and pS82. (D) RNAi-mediated knockdown of RSK2 resulted in reduction in phosphorylation levels of CREB in RSK2-expressing M4e, 212LN, and 37B HNSCC cells and decreased Hsp27 S78 phosphorylation in M4e and 212LN cells but not 37B cells. (E) RNAi-mediated knockdown of RSK2 resulted in reduction in the phosphorylation level of Hsp27 S82 in M4e and 212LN cells but not 37B cells.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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