Ofer 2015 Mol Endocrinol
|Ofer P, Heidegger I, Eder IE, Schöpf B, Neuwirt H, Geley S, Klocker H, Massoner P (2015) Both IGF1R and INSR knockdown exert anti-tumorigenic effects in prostate cancer in vitro and in vivo. Mol Endocrinol 29:1694-707.|
Abstract: The insulin-like growth factor (IGF) network with its main receptors insulin-like growth factor receptor 1 (IGF1R) and insulin receptor (INSR) is of major importance for cancer initiation and progression. To date clinical studies targeting this network were disappointing and call for thorough analysis of the IGF network in cancer models. We highlight the oncogenic effects controlled by IGF1R and INSR in prostate cancer cells and show similarities as well as differences after receptor knockdown (KD). In PC3 prostate cancer cells stably transduced with inducible short hairpin RNAs (shRNA) targeting IGF1R or INSR attenuated cell growth and proliferation ultimately driving cells into apoptosis. IGF1R KD triggered rapid and strong anti-proliferative and pro-apoptotic responses whereas these effects were less pronounced and delayed after INSR KD. Downregulation of the anti-apoptotic proteins Mcl-1 and survivin was observed in both knockdowns whereas IGF1R KD also attenuated expression of pro-survival proteins Bcl-2 and Bcl-xL. Receptor KD induced cell death involved autophagy in particular upon IGF1R KD, however no difference in mitochondrial energy metabolism was observed. In a mouse xenograft model induction of IGF1R or INSR KD after tumor establishment eradicated most of the tumors. After 20 days of receptor KD tumor cells were found only in 1/14 IGF1R and 3/14 INSR KD tumor remnants. Collectively, our data underline the oncogenic functions of IGF1R and INSR in prostate cancer namely growth, proliferation and survival in vitro as well as in vivo and identify Mcl-1 and survivin as important mediators of inhibitory and apoptotic effects.
• Keywords: PC3 cells
• O2k-Network Lab: AT Innsbruck Oroboros
Labels: MiParea: Respiration, Genetic knockout;overexpression Pathology: Cancer Stress:Cell death Organism: Human Tissue;cell: Genital, Other cell lines Preparation: Intact cells, Permeabilized cells
Coupling state: ROUTINE, OXPHOS, ET Pathway: F, N, NS HRR: Oxygraph-2k