Osteopontin increases lung cancer cells migration via activation of the alphavbeta3 integrin/FAK/Akt and NF-kappaB-dependent pathway.
Tumor malignancy is associated with several features such as proliferation ability and frequency of metastasis. Osteopontin (OPN), which is abundantly expressed in bone matrix, is involved in cell adhesion, migration, invasion and cell proliferation via interaction with its receptor, alphavbeta3 integrin. However, the effect of OPN on migration activity in human lung cancer cells is mostly unknown. Here we found that OPN increased the migration via activation of alphavbeta3 integrin in human lung cancer cells (A549 cells). Phosphatidylinositol 3-kinase inhibitor (PI3K; Ly294002), Akt inhibitor or ERK inhibitor (PD98059) inhibited the OPN-induced increase in the migration of lung cancer cells. OPN stimulation increased the phosphorylation of focal adhesion kinase (FAK), p85 subunit of PI3K, serine 473 of Akt and ERK. In addition, treatment of A549 cells with NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) inhibited OPN-induced migration of lung cancer cells. Stimulation of A549 cells with OPN also induced IkappaB kinase alpha/beta (IKK alpha/beta) phosphorylation, IkappaBalpha phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. The OPN-mediated increases in IKK alpha/beta, IkappaBalpha and p65 Ser(536) phosphorylation were inhibited by Ly294002, Akt inhibitor and PD98059. Co-transfection with FAK, p85, Akt and ERK mutants also reduced the OPN-induced kappaB-luciferase activity. Taken together, these results suggest that OPN acts through alphavbeta3 integrin, which in turn activates the FAK, PI3K, Akt, ERK and NF-kappaB pathways, contributing to the migration of lung cancer cells.
Fong
Yi-Chin
YC
Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan.
Liu
Shan-Chi
SC
Huang
Chun-Yin
CY
Li
Te-Mao
TM
Hsu
Sheng-Feng
SF
Kao
Shung-Te
ST
Tsai
Fuu-Jen
FJ
Chen
Wen-Chi
WC
Chen
Chih-Yi
CY
Tang
Chih-Hsin
CH
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D051058:Oncogene Protein v-akt; D053495:Osteopontin / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013859:Thiocarbamates / Q000494:pharmacology; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology
D002867:Chromones; D005419:Flavonoids; D039302:Integrin alphaVbeta3; D009025:Morpholines; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013859:Thiocarbamates; D053495:Osteopontin; C066229:prolinedithiocarbamate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D014108:Tosylphenylalanyl Chloromethyl Ketone; D011392:Proline; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051058:Oncogene Protein v-akt; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one