Activation of the insulin-like growth factor-I receptor inhibits tumor necrosis factor-induced cell death

Abstract

The effect of insulin-like growth factor (IGF) on tumor necrosis factor (TNF)-induced cell killing was determined for mouse BALB/c3T3 fibroblasts in vitro. Cells maintained in 0.5% fetal bovine serum (FBS) were killed by TNF within 6 h in a concentration-dependent manner, an effect that was prevented by IGF-I. TNF-induced cytotoxicity of 3T3 cells that overexpress the human IGF-I receptor (p6 cells) was prevented by IGF-I alone in the absence of serum. TNF-induced cell death was associated with the morphologic features of apoptosis and the release of low-molecular-weight DNA, both of which were prevented by IGF-I. Neither epidermal growth factor (EGF) nor platelet-derived growth factor (PDGF) protected p6 cells from TNF-induced apoptosis. The specific protective action of the IGF-I receptor was demonstrated further by the marked sensitivity to TNF of embryo fibroblasts derived from mice with targeted disruption of the IGF-I receptor (R-cells) but not of fibroblasts derived from wild-type littermates or R-cells transfected with the cDNA for the human IGF-I receptor. Cycloheximide or actinomycin D markedly reduced the protection offered by IGF-I. IGF-I protection of BALB/c3T3 cells persisted for up to 5 days in the presence of PDGF and EGF, whereas IGF-I lost its effectiveness after 2 days in the absence of growth factors. IGF-I did not prevent TNF-induced release of arachidonic acid. The results demonstrate a specific role for the IGF-I receptor in the protection against TNF cytotoxicity. This action of the IGF-I receptor is mediated by protective cytosolic proteins that exhibit a high rate of turnover and whose levels are regulated principally by factors within serum other than IGF-I.

Differential expression and translocation of protein tyrosine phosphatase 1B-related proteins in ME-180 tumor cells expressing apoptotic sensitivity and resistance to tumor necrosis factor: potential interaction with epidermal growth factor receptor

“…Recent studies of cellular apoptotic sensitivity suggest that growth factors which transduce their proliferative signals through activation of a tyrosine kinase cascade can modulate cellular sensitivity to a variety of apoptotic signals (Wu et al, 1996;Gardner and Johnson, 1996;Tilly et al, 1992;Garcia-Lloret, 1996). These studies parallel those previously described for the protective e ects of speci®c growth factors which activate receptor tyrosine kinases and inhibit TNF-induced apoptosis (Sugarman et al, 1987).…”

“…Several reports have demonstrated that growth factors which activate receptor tyrosine kinases are able to delay or prevent apoptosis driven by TNF and other stimuli (Gardner and Johnson, 1996;Tilly et al, 1992;Garcia-Lloret et al, 1996;Sugarman et al, 1987;Shephard and Lewis, 1988;Nishikawa et al, 1994;Aggarwal et al, 1994;Wu et al, 1995) whereas ampli®ed expression of tyrosine kinases may constitutively activate survival signals and reduce the apoptotic actions of TNF (Wu et al, 1996;Gardner and Johnson, 1996;Garcia-Lloret et al, 1996;Sugarman et al, 1987;Hudziak et al, 1988;Lewis, 1988, Nishikawa et al, 1994;Aggarwal et al, 1994). In earlier studies we presented evidence of a role for overexpression of EGFr in loss of TNF sensitivity in two squamous carcinoma cell lines and subsequently demonstrated that inhibition of EGFr enzymatic activity with tyrphostin increased sensitivity to TNF (Nishikawa et al, 1994;Donato et al, 1993;Perez and Donato, 1996).…”

“…Although enforced expression of bcl-2 and bcl-x can inhibit TNF-mediated ME-180 cell death (Jaattela et al, 1995), we were unable to detect expression of these molecules in either Sen or Res ME-180 cells. Since EGF and insulin have been demonstrated to increase cell survival and alter TNF-induced cytotoxicity (Eastman, 1995;Merlo et al, 1995;Wu et al, 1996;Garcia-Lloret et al, 1996;Sugarman et al, 1987), we investigated potential antagonism between TNF and survival pathways controlled by receptor tyrosine kinases.…”

Overexpression of CEACAM6 promotes insulin-like growth factor I-induced pancreatic adenocarcinoma cellular invasiveness

“…IGF-IR is overexpressed by a variety of human malignancies, including pancreatic adenocarcinoma (Bergmann et al, 1995;Ouban et al, 2003). Numerous studies have demonstrated that both overexpression and overactivity of IGF-IR are associated with malignant transformation, increased tumor aggressiveness and protection from apoptosis (Kaleko et al, 1990;Macaulay, 1992;Sell et al, 1995;Wu et al, 1996;Prisco et al, 1997). Circulating IGF-I levels modulate gastrointestinal tumor growth and liver metastasis in vivo (Wu et al, 2002), and IGF-I stimulates cellular invasiveness and metastasis in human tumors including pancreatic adenocarcinoma (Stracke et al, 1989;Long et al, 1998a b;Tanno et al, 2001).…”

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

“…22 Overexpression of IGF-IR protects cells from UV irradiation-, cytokine-and gamma radiation-induced apoptosis. [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.…”