Involvement of p38alpha mitogen-activated protein kinase in lung metastasis of tumor cells.
To study the role of p38 mitogen-activated protein kinase (p38) activity during the process of metastasis, p38alpha(+/-) mice were subjected to an in vivo metastasis assay. The number of lung colonies of tumor cells intravenously injected in p38alpha(+/-) mice was markedly decreased compared with that in wild-type (WT) mice. On the other hand, the time-dependent increase in tumor volume after subcutaneous tumor cells transplantation was comparable between WT and p38alpha(+/-) mice. Platelets of p38alpha(+/-) mice were poorly bound to tumor cells in vitro and in vivo compared with those of WT mice. E- and P-selectin mRNAs were markedly induced in the lung after intravenous injection of tumor cells. However, the induction of these selectin mRNAs in p38alpha(+/-) mice was weaker than that in WT mice. Furthermore, the resting expression levels of E-selectin in lung endothelial cells and P-selectin in platelets of p38alpha(+/-) mice were suppressed compared with those of WT mice. The number of tumor cells attached on lung endothelial cells of p38alpha(+/-) mice was significantly reduced compared with that of WT mice. The transmigrating activity of tumor cells through lung endothelial cells of p38alpha(+/-) mice was similar to that of WT mice. These results suggest that p38alpha plays an important role in extravasation of tumor cells, possibly through regulating the formation of tumor-platelet aggregates and their interaction with the endothelium involved in a step of hematogenous metastasis.
Matsuo
Yuji
Y
Departments of Biochemistry and Molecular Pharmacology, Respirology, and Molecular Pathology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
Amano
Shinya
S
Furuya
Mitsuko
M
Namiki
Kana
K
Sakurai
Kanako
K
Nishiyama
Mariko
M
Sudo
Tatsuhiko
T
Tatsumi
Koichiro
K
Kuriyama
Takayuki
T
Kimura
Sadao
S
Kasuya
Yoshitoshi
Y
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D045744:Cell Line, Tumor; D003433:Crosses, Genetic; D019040:E-Selectin / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008546:Melanoma, Experimental / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism / Q000502:physiology*; D009362:Neoplasm Metastasis; D019007:P-Selectin / Q000378:metabolism; D011485:Protein Binding; D013997:Time Factors
D019040:E-Selectin; D019007:P-Selectin; D048308:Mitogen-Activated Protein Kinase 14