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 April 1, 2010; First published March 15, 2010
Citation Information: J Clin Invest. 2010;120(4):1165-1177. https://doi.org/10.1172/JCI40582.
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Categories: Research Article Oncology

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

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 2

Expression of RSK2 promotes in vitro HNSCC cell invasion.

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Expression of RSK2 promotes in vitro HNSCC cell invasion. (A) Enforced e...
(A) Enforced expression of RSK2 resulted in increased invasive ability in poorly metastatic HNSCC cells, including 686LN, Tu212, and 37A, in the in vitro Matrigel invasion assay. Relative invasion was normalized to the invasion of control cells without transfection (mean ± SD). **P < 0.01, by 2-tailed Student’s t test. (B) Treatment with RSKI-fmk (6 μM) effectively decreased RSK2 kinase activity, as assessed by phosphorylation level of S386, in RSK2-expressing M4e, 212LN, and 37B cells. (C) Representative areas show that inhibition of RSK2 by RSKI-fmk treatment decreased the numbers of M4e and 212LN cells that crossed the Matrigel in the invasion assay. Original magnification, ×50. (D and E) Inhibition of RSK2 by RSKI-fmk (D) or BI-D1870 (E) (6 μM) decreased invasive ability of M4e, 212LN, and 37B cells. Relative invasion was normalized to the invasion of control cells without drug treatment (mean ± SD; *P = 0.01–0.05). (F) Targeting RSK2 by RSKI-fmk or BI-D1870 (6 μM) did not significantly affect the proliferation rate of M4e, 212LN, and 37B cells (mean ± SD). Cell number of each sample was determined by normalizing the cell viability to that of a standard curve of cell number.