Increased Insulin-Like Growth Factor I Receptor Expression and Signaling Are Components of Androgen-Independent Progression in a Lineage-Derived Prostate Cancer Progression Model

Abstract

Apoptosis and inhibition of mitosis are primary mechanisms mediating androgen ablation therapy-induced regression of prostate cancer (PCa). However, PCa readily becomes androgen independent, leading to fatal disease. Up-regulated growth and survival signaling is implicated in development of resistance to androgen ablation therapy. We are testing the hypothesis that insulin-like growth factor (IGF) responsiveness is required for androgen-independent (AI) progression. Using the LNCaP human PCa progression model, we have determined that IGF-I-mediated protection from apoptotic stress and enhanced mitotic activity is androgen dependent in LNCaP cells but is androgen independent in lineage-derived C4-2 cells. Both cell lines exhibit androgen-responsive patterns of IGF-I receptor (IGF-IR) expression, activation, and signaling to insulin receptor substrate-2 and AKT. However, C4-2 cells express higher levels of IGF-IR mRNA and protein and exhibit enhanced IGF-I-mediated phosphorylation and downstream signaling under androgen-deprived conditions. In comparisons of naïve and AI metastatic human PCa specimens, we have confirmed that IGF-IR levels are elevated in advanced disease. Together with our LNCaP/C4-2 AI progression model data, these results indicate that increased IGF-IR expression is associated with AI antiapoptotic and promitotic IGF signaling in PCa disease progression.

PTEN and GSK3β: key regulators of progression to androgen-independent prostate cancer

“…Thus, an attractive hypothesis is that IGF-1 enhancement of growth and proliferation may occur as a result of stabilization, nuclear localization of b-catenin and enhanced b-catenin/AR interactions . These observations are consistent with the finding that IGF-1R increases substantially in AI PrCa systems (Krueckl et al, 2004) and that PTEN also regulate levels of IGF-1R (Zhao et al, 2004). Use of monoclonal antibodies, interfering RNAs, antisense oligonucleotides or small molecule inhibitors (e.g.…”

“…While it has been argued that the GSK3 pools associated with Wnt and PI3K/Akt pathways are different (Ding et al, 2000), it has become increasingly apparent that PI3K and Wnt/bcat can crossregulate via GSK3b pools as elicited by upstream activators such canonical Wnts and IGFs. Autocrine production of IGF-1 and increased IGF1-R levels are both correlated with progressive PrCa and systems harbouring enhanced activity of the PI3K/Akt axis (Nickerson et al, 2001;Krueckl et al, 2004). Complexing of IGF-1 with the IGF-1R enhances AR transactivation and endogenous PSA production (Culig et al, 1994).…”

IGF-I receptor phosphorylation is impaired in cathepsin X-deficient prostate cancer cells

“…Similarly to the mRNA level, unstimulated cells expressed higher protein levels of the IGF-IR after cathepsin X knockdown (Figure 2 ). Overall, the expression of the IGF-IR was higher in PC-3 cells ( Figure 2A) compared with LNCaP cells (Figure 2D), which is in good agreement with data from the literature (Krueckl et al , 2004 ;Pandini et al , 2005 ). In cells deficient of cathepsin X, stimulation with IGF-I resulted in reduced phosphorylation compared with control cells.…”

Superior Antitumor Activity of a Novel Bispecific Antibody Cotargeting Human Epidermal Growth Factor Receptor 2 and Type I Insulin-like Growth Factor Receptor

“…Elevated IGF-IR is found in many tumor malignancies, including breast, prostate, and lung cancers (18,19). In addition, overexpression of IGF-IR has been associated with disease progression and cancer metastasis (20,21).…”