Validation of the type 1 insulin-like growth factor receptor as a therapeutic target in renal cancer

Abstract

Purpose: Expression of the type 1 insulin-like growth factor receptor (IGF1R) confers adverse prognosis in clear cell renal cell cancer (CC-RCC). We recently showed that IGF1R expression is inhibited by the von Hippel-Lindau (VHL) tumor suppressor, and the IGF1R is up-regulated in CC-RCC, in which VHL is frequently inactivated. We tested the hypothesis that IGF1R up-regulation mediates resistance to cancer therapeutics, evaluating the effects of IGF1R depletion on sensitivity to cytotoxic drugs, which are ineffective in RCC, and the mammalian target of rapamycin (mTOR) inhibitor rapamycin, analogues of which have clinical activity in this tumor. Experimental Design: This study used CC-RCC cells harboring mutant VHL, and isogenic cells expressing functional VHL. Cells were transfected with nonsilencing control small interfering RNA (siRNA), or with one of two different IGF1R siRNAs. The more potent siRNA was modified by 2′-O-methyl derivatization for in vivo administration. Results: CC-RCC cells expressing mutant VHL and higher IGF1R were more chemoresistant than cells expressing functional VHL. IGF1R depletion induced apoptosis, blocked cell survival, and sensitized to 5-fluorouracil and etoposide. These effects were significantly greater in CC-RCC cells expressing mutant VHL, supporting the hypothesis that IGF1R up-regulation makes a major contribution to the chemoresistance associated with VHL loss.

Engagement of β-arrestin by transactivated insulin-like growth factor receptor is needed for V2 vasopressin receptor-stimulated ERK1/2 activation

“…Although these metalloproteinases were selected largely for their action on the cellular matrix that could prevent invasion, their role in controlling MAPK activation by GPCRs could also be part of their action mechanism. IGFR for its part has been shown to increase kidney cell growth (73,74) and has been identified as a potential target for the treatment of some renal cancers (75,76). Future work will be required to establish the identity of the metalloproteinase and the processed IGFR ligand involved in the pathway in order to design the experiments to directly test the importance of the V2R-stimulated ERK1/2 pathway in normal and pathological conditions.…”

Cancer cells promote survival through depletion of the von Hippel–Lindau tumor suppressor by protein crosslinking

“…IGF-1R is a key mediator of tumor cell survival and is overexpressed in many cancers (Casa et al, 2008;Yuen et al, 2009). IGF-1R is downregulated by VHL in an HIF-1a-independent manner (Yuen et al, 2009).…”

“…IGF-1R is downregulated by VHL in an HIF-1a-independent manner (Yuen et al, 2009). VHL decreases IGF-1R transcription and mRNA stability, resulting in the inhibition of renal tumorigenesis and chemosensitivity in renal cell carcinoma (Yuen et al, 2007).…”

“…This pathway may have a key role in the acquisition of drug resistance by cancer cells and cancer progression. TGase-2-mediated VHL depletion increases the levels of IGF-1R, a known actuator of Akt-and mitogen-activated protein kinase signaling pathways that stabilize HIF-1a and HIF-2a and upregulate vascular endothelial growth factor in renal cell carcinoma (Yuen et al, 2009) and EPO, a known the primary humoral regulator of mammalian erythropoiesis resulting in an increased blood oxygen-carrying capacity (Wang and Semenza, 1993). The results of this study provide compelling support for TGase 2 as a viable therapeutic target for a novel approach to cancer treatment.…”

Apicidin-Resistant HA22T Hepatocellular Carcinoma Cells strongly activated the Wnt/β-Catenin Signaling Pathway and MMP-2 Expression via the IGF-IR/PI3K/Akt Signaling Pathway Enhancing Cell Metastatic Effect

“…[58][59][60] IGF-IR makes a significant contribution to resistance to clinical therapy. 61) In this particular study, the authors investigated the cts of the -catenin and IGF-IR/PI3K/Akt pathways on metastasis in apicidin-resistant HA22T cells.…”