We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
184: Targeting the type 1 insulin-like growth factor receptor (IGF1R) in renal cancer.
- Authors
Yuen, John S. P.; Cockman, Matthew E.; Sullivan, Mark; Protheroe, Andrew; Pugh, Christopher W.; Werner, Haim; Macaulay, Valentine M.
- Abstract
Introduction: The type 1 insulin-like growth factor receptor (IGF1R) mediates many key aspects of the malignant phenotype. Clear cell renal cell carcinoma (CC-RCC) is a highly chemoresistant tumour that is characterised by frequent inactivating mutation of the von Hippel-Lindau (VHL) gene. In CC-RCC cells, IGF1R protein levels were not affected by hypoxia, but were higher in cells harbouring inactivating VHL mutations than in isogenic cells expressing wild-type (WT) VHL. Steady-state IGF1R mRNA and IGF1R promoter activity were significantly lower in CC-RCC cells expressing WT VHL compared with parental cells, consistent with a transcriptional effect. VHL was shown to sequester Sp1 and HuR to suppress IGF1R expression at the level of transcription and mRNA stability. This represents a new, non-HIF-dependent role for VHL. IGF1R mRNA levels were found to be significantly higher in biopsies of CC-RCC than benign kidney, confirming the clinical relevance of these findings. Methods: We proceeded to test the hypothesis that IGF1R upregulation contributes to the survival and chemoresistance of CC-RCC cells. Results: IGF1R depletion using sequence-specific IGF1R siRNA was found to block survival of CC-RCC cells expressing either mutant (MT) or WT VHL. Moreover, IGF1R gene silencing was found to induce sensitisation to 5-fluorouracil (5-FU) in CC-RCC cells expressing MT but not WT VHL, supporting the hypothesis that the IGF1R upregulation that follows VHL inactivation contributes to chemoresistance. IGF1R knockdown also sensitised MT VHL CC-RCC cells to etoposide, zoledronate and rapamycin but not to cisplatin. Conclusions: These findings suggest that anti-IGF1R strategies may be of therapeutic benefit in advanced CC-RCC patients.
- Subjects
GENE silencing; CELL receptors; SOMATOMEDIN; RENAL cell carcinoma; GENETIC mutation; MESSENGER RNA; PROMOTERS (Genetics)
- Publication
Indian Journal of Urology, 2008, Vol 24, pS115
- ISSN
0970-1591
- Publication type
Article