Alteration of cell growth and morphology by overexpression of transforminggrowth factor beta type II receptor in human lung adenocarcinoma cells

TGF-beta is a potent inhibitory regulator of cell growth. which is transduc ed 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 i nvestigated the expression of RI and RII in 13 human non-small cell lung ca ncer cell lines (NSCLCs) and demonstrated decreased or loss of RII expressi on 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 recombin ant retrovirus expressing full-length TGF-beta RI1. Stably transfected cell s showed significant increase in RII mRNA and protein expression. These cel ls responded to exogenous TGF-beta1 with suppressed proliferation in a dose -dependent manner and G1 arrest accompanied by morphological change distinc t from control cells. We also investigated whether overexpression of domina nt-negative RII (dnRII) in NCI-H441 adenocarcinoma. which is sensitive but expresses low levels of RII. could block signaling through the receptor com plex. 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 cl ose association between the loss of the expression of wild-type TGF-beta RI I and carcinogenesis in human lune cancer cells. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.