Alteration of cell growth and morphology by overexpression of transforming growth factor beta type II receptor in human lung adenocarcinoma cells.
TGF-beta is a potent inhibitory regulator of cell growth, which is transduced through interaction between type I (RI) and type II (RII) receptors that form heteromeric kinase complexes. Abnormal expression of these receptors has been identified in several human epithelial cancers and has been shown to be highly associated with resistance to TGF-beta. In this study, we investigated the expression of RI and RII in 13 human non-small cell lung cancer cell lines (NSCLCs) and demonstrated decreased or loss of RII expression in five lung cancer cell lines, but not of RI. Of these cell lines, the role of RII in NCI-H358 adenocarcinoma, which lacks RII and is insensitive to TGF-beta, was investigated by transducing this cell line with a recombinant retrovirus expressing full-length TGF-beta RII. Stably transfected cells showed significant increase in RII mRNA and protein expression. These cells responded to exogenous TGF-beta1 with suppressed proliferation in a dose-dependent manner and G1 arrest accompanied by morphological change distinct from control cells. We also investigated whether overexpression of dominant-negative RII (dnRII) in NCI-H441 adenocarcinoma, which is sensitive but expresses low levels of RII, could block signaling through the receptor complex. The overexpression of this kinase-domain-truncated RII by expressing the retroviral dnRII construct led to loss of the ability to respond to TGF-beta1 and an exhibition of uncontrolled growth. These results suggest a close association between the loss of the expression of wild-type TGF-beta RII and carcinogenesis in human lung cancer cells.
Kim
T K
TK
Department of Internal Medicine, College of Medicine and Lung Institute, SNUMRC, Seoul National University and Clinical Research Institute, Seoul National University Hospital, Seoul 110-744, South Korea.
Mo
E K
EK
Yoo
C G
CG
Lee
C T
CT
Han
S K
SK
Shim
Y S
YS
Kim
Y W
YW
D000230:Adenocarcinoma / Q000473:pathology / Q000503:physiopathology*; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D019925:Cyclin A / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis* / Q000502:physiology; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D019925:Cyclin A; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta