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

Abstract

Overexpression or activation of insulin-like growth factor I receptor (IGF-IR) has been observed in many human cancers including breast, lung, colon and gastric carcinomas. We demonstrate that inhibition of the endogenous insulin-like growth factor I receptor by stable expression of a dominant-negative IGF-IR represses the transforming activity in vitro and tumorigenicity of human lung carcinoma cells A549 in vivo. The suppression of tumorigenicity in nude mice is correlated with the induction of glandular dierentiation. In addition, functional inhibition of the endogenous receptor dramatically increases the sensitivity of A549 cells to a variety of apoptotic signals including UV irradiation and proteasome inhibitors. These eects are due to the formation of a stable heterocomplex of the dominant-negative receptor with the endogenous wild type receptor which reduces the kinase activity of the latter by twofold. Thus, inhibition of the IGF-IR signaling pathway not only suppresses tumorigenicity but also enhances sensitivity to apoptosis-inducing agents. Antagonizing IGF-IR signaling by promoting tumor dierentiation and enhancing sensitivity to apoptotic death are potential cancer therapeutic approaches.

A recombinant humanized anti‐insulin‐like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti‐epidermal growth factor receptor therapy against human cancer xenografts

“…We also showed that 7C10 is able to inhibit significantly the in vivo growth of A549 cells. This latter result is in agreement with the report of Jiang et al 31 who described that a dominant-negative IGF-IR induced tumor suppression of A549 lung carcinoma cells. At least 3 mechanisms can be related to the observed antibody efficacy for both 7C10 and h7C10: inhibition of IGF-IR-mediated signal transduction, inhibition of cell cycle progression and degradation of the receptor.…”

“…[22][23][24] Recent studies suggested that the molecular alteration that results in enhanced activation of IGF-IR pathways could represent one mechanism of resistance to trastuzumab, a humanized antibody against HER2/neu, used in breast cancer therapy. 25,26 Strategies using either murine monoclonal antibodies, [27][28][29][30] dominant-negatives mutants 31 or antisense oligonucleotides 32 directed against IGF-IR mRNA have been reported to inhibit in vitro and/or in vivo tumor proliferation.…”

Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells

“…We also studied the effect of IGF-1 on STAT activity in lung carcinoma cells given previous findings demonstrating the ability of IGF-1 to stimulate the growth of serum-deprived lung cancer cells and targeting the IGF-1 receptor can lead to tumor suppression (Ankrapp and Bevan, 1993;Favoni et al, 1994;Jiang et al, 1999). Despite the reported presence of IGF-1 receptors on the surface of A549 lung carcinoma cells, we were unable to convincingly demonstrate that addition of IGF-1 to these cells stimulated the DNA-binding activity of Stat3.…”

Inhibition of anchorage-independent growth and lung metastasis of A549 lung carcinoma cells by IκBβ

“…We have previously shown that expression of dominant-negative IGF-I receptor (IGF-IR) in A549 cells inhibited colony formation in soft agar (Jiang et al, 1999). Recently, the c-Jun N-terminal kinase 2 (JNK2) has been shown to be required for EGFstimulated anchorage-independent growth of A549 cells (Bost et al, 1999).…”

“…We have recently reported that expression of dominant-negative IGF-I receptor in A549 lung carcinoma cells suppressed anchorageindependent growth and tumorigenicity in nude mice and sensitized cells to apoptosis-inducing agents (Jiang et al, 1999). Like that of dominant-negative IGF-I receptor, expression of IkBb in A549 cells also inhibited anchorage-independent growth and sensitized cells to apoptosis induced by proteasome inhibitors.…”