p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cells.
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.
Kang
Sumin
S
Winship Cancer Institute of Emory University, Atlanta, Georgia 30322, USA. smkang@emory.edu
Elf
Shannon
S
Lythgoe
Katherine
K
Hitosugi
Taro
T
Taunton
Jack
J
Zhou
Wei
W
Xiong
Li
L
Wang
Dongsheng
D
Muller
Susan
S
Fan
Songqing
S
Sun
Shi-Yong
SY
Marcus
Adam I
AI
Gu
Ting-Lei
TL
Polakiewicz
Roberto D
RD
Chen
Zhuo Georgia
ZG
Khuri
Fadlo R
FR
Shin
Dong M
DM
Chen
Jing
J
D000199:Actins / Q000737:chemistry; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018450:Disease Progression; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D051379:Mice; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*
D000199:Actins; D017362:Cyclic AMP Response Element-Binding Protein; D055551:HSP27 Heat-Shock Proteins; D034741:RNA, Small Interfering; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3