Induction of tumor suppression and glandular differentiation of A549 lung carcinoma cells by dominant-negative IGF-I receptor

Overexpression or activation of insulin-like growth factor I receptor (IGF- IR) has been observed in many human cancers including breast, lung, colon a nd gastric carcinomas, We demonstrate that inhibition of the endogenous ins ulin-like growth factor I receptor by stable expression of a dominant-negat ive IGF-IR represses the transforming activity in vitro and tumorigenicity of human lung carcinoma cells A549 in vivo, The suppression of tumorigenici ty in nude mice is correlated with the induction of glandular differentiati on. In addition, functional inhibition of the endogenous receptor dramatica lly increases the sensitivity of A549 cells to a variety of apoptotic signa ls including UV irradiation and proteasome inhibitors. These effects are du e to the formation of a stable heterocomplex of the dominant-negative recep tor with the endogenous wild type receptor which reduces the kinase activit y of the latter by twofold. Thus, inhibition of the IGF-IR signaling pathwa y not only suppresses tumorigenicity but also enhances sensitivity to apopt osis-inducing agents. Antagonizing IGF-IR signaling by promoting tumor diff erentiation and enhancing sensitivity to apoptotic death are potential canc er therapeutic approaches.