Both IGF1R and INSR Knockdown Exert Antitumorigenic Effects in Prostate Cancer In Vitro and In Vivo.

Abstract

The IGF network with its main receptors IGF 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, targeting IGF1R or INSR attenuated cell growth and proliferation ultimately driving cells into apoptosis. IGF1R KD triggered rapid and strong antiproliferative and proapoptotic responses, whereas these effects were less pronounced and delayed after INSR KD. Down-regulation of the antiapoptotic proteins myeloid cell leukemia-1 and survivin was observed in both KDs, whereas IGF1R KD also attenuated expression of prosurvival proteins B cell lymphoma-2 and B cell lymphoma-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 myeloid cell leukemia-1 and survivin as important mediators of inhibitory and apoptotic effects.

• Authors: Philipp Ofer, Isabel Heidegger, Iris E Eder, Bernd Schöpf, Hannes Neuwirt, Stephan Geley, Helmut Klocker, Petra Massoner
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 29 Issue 12 Pg. 1694-707 (Dec 2015) ISSN: 1944-9917 [Electronic] United States
• PMID: 26452103 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• RNA, Small Interfering
• INSR protein, human
• Receptor, IGF Type 1
• Receptor, Insulin

Topics

• Animals
• Antigens, CD (genetics, metabolism)
• Apoptosis (genetics, physiology)
• Cell Line, Tumor
• Cell Proliferation (genetics, physiology)
• Cell Survival (genetics, physiology)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Prostatic Neoplasms (genetics, metabolism)
• RNA, Small Interfering (genetics, physiology)
• Receptor, IGF Type 1 (genetics, metabolism)
• Receptor, Insulin (genetics, metabolism)
• Signal Transduction (genetics, physiology)
• Xenograft Model Antitumor Assays