TGF-beta1 increases motility and alphavbeta3 integrin up-regulation via PI3K, Akt and NF-kappaB-dependent pathway in human chondrosarcoma cells.
Transforming growth factor-beta1 (TGF-beta1) plays an essential role in tumor progression and metastasis. Integrins are the major adhesive molecules in mammalian cells. Here we found that TGF-beta1 increased the migration and cell surface expression of alphavbeta3 integrin in human chondrosarcoma cells (JJ012 cells). Phosphatidylinositol 3-kinase inhibitor (PI3K; Ly294002) or Akt inhibitor inhibited the TGF-beta1-induced increase the migration of chondrosarcoma cells. TGF-beta1 stimulation increased the phosphorylation of p85 subunit of PI3K, and serine 473 of Akt. In addition, treatment of JJ102 cells with NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) inhibited TGF-beta1-induced cells migration and integrins expression. Treatment of JJ012 cells with TGF-beta1-induced IkappaB kinase alpha/beta (IKKalpha/beta) phosphorylation, IkappaBalpha phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. The TGF-beta1-mediated increases in IKKalpha/beta phosphorylation and p65 Ser(536) phosphorylation were inhibited by Ly294002 and Akt inhibitor. Cotransfection with p85 and Akt mutants also reduced the TGF-beta1-induced kappaB-luciferase activity. Taken together, these results suggest that the TGF-beta1 acts through PI3K/Akt, which in turn activates IKKalpha/beta and NF-kappaB, resulting in the activations of alphavbeta3 integrins and contributing the migration of chondrosarcoma cells.
Yeh
Ying-Yi
YY
School of Dental Hygiene, China Medical University, Taichung, Taiwan.
Chiao
Chung-Chieh
CC
Kuo
Wen-Yen
WY
Hsiao
Yu-Chun
YC
Chen
Ying-Ju
YJ
Wei
Ying-Ying
YY
Lai
Tzu-Hsu
TH
Fong
Yi-Chin
YC
Tang
Chih-Hsin
CH
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002813:Chondrosarcoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D015854:Up-Regulation
D039302:Integrin alphaVbeta3; D016328:NF-kappa B; D051996:Transcription Factor RelA; D053773:Transforming Growth Factor beta1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase