Comparison of three approaches for inhibiting insulin-like growth factor I receptor and their effects on NSCLC cell lines in vitro
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A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Daria Cosaceanu1, Mia Carapancea, Oana Alexandru
1Department of Oncology-Pathology, Cancer Center Karolinska and Radiumhemmet Karolinska Institute/Hospital. R8:00, Stockholm, S-171 76. Sweden.
Abstract:
The insulin-like growth factor-1 receptor (IGF-1R) mitogenic signaling mediates malignant cell survival by many complex and redundant pathways. This study compared the effects of IGF-1R inhibition on viability and apoptosis of two NSCLC cell lines, using three different methods for the impairment of IGF-1R function: (IR3, an anti-IGF-1R antibody; tyrphostin AG1024, a tyrosine kinase inhibitor (TKI) and IGF-1R-small interfering RNA (siRNA). IGF-1R inhibition led to a decrease of cell survival and induced apoptosis in a manner depending on the approach used for the receptor inhibition. To find an explanation, we analyzed the effects of these treatments on three major antiapoptotic pathways evoked by IGF-1R signaling: IRS-1, Shc and 14.3.3-dependent mitochondrial translocation of Raf-1 kinase (mitRaf). (IR3 downregulated IRS-1 phosphorylation in A549 cells and Shc phosphorylation in U1810 cells. While in A549 cells AG1024 treatment decreased both IRS-1 and Shc phosphorylation, in U1810 cells the IRS-1 phosphorylation was only slightly affected and the Shc phosphorylation drastically downregulated. Neither (IR3 nor AG1024 had any effect on Raf-1 kinase translocation. Irrespective of the cell line, IGF-1R-siRNA treatment induced downregulation of both IRS-1 and Shc phosphorylation coupled with the abrogation of mitRaf. In addition, the IGF-1R-siRNA proved to be the most potent inducer of apoptosis suggesting that more than one antiapoptotic pathway in IGF-1R signaling should be inhibited to effectively induce apoptosis in lung cancer cells.
Insights
Inhibiting the insulin-like growth factor-1 receptor (IGF-1R) reduces non-small cell lung cancer (NSCLC) cell survival and induces apoptosis. Combining multiple inhibition methods, particularly IGF-1R-small interfering RNA (siRNA), is most effective for triggering cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Insulin-like growth factor-1 receptor (IGF-1R) signaling is crucial for malignant cell survival through complex, redundant pathways.
- Targeting IGF-1R is a potential strategy for non-small cell lung cancer (NSCLC) therapy.
Purpose of the Study:
- To compare the efficacy of different IGF-1R inhibition methods on NSCLC cell viability and apoptosis.
- To elucidate the impact of IGF-1R inhibition on key antiapoptotic signaling pathways.
Main Methods:
- Utilized three distinct methods to inhibit IGF-1R: (IR3 antibody, AG1024 tyrosine kinase inhibitor (TKI), and IGF-1R-small interfering RNA (siRNA).
- Assessed effects on cell survival and apoptosis in two NSCLC cell lines (A549 and U1810).
- Analyzed alterations in phosphorylation of IRS-1, Shc, and mitochondrial translocation of Raf-1 kinase (mitRaf).
Main Results:
- IGF-1R inhibition decreased cell survival and induced apoptosis, with varying potency depending on the method.
- (IR3 and AG1024 showed differential effects on IRS-1 and Shc phosphorylation and did not affect mitRaf.
- IGF-1R-siRNA significantly downregulated both IRS-1 and Shc phosphorylation, abrogated mitRaf, and was the most potent inducer of apoptosis.
Conclusions:
- Effective induction of apoptosis in NSCLC cells requires simultaneous inhibition of multiple IGF-1R-mediated antiapoptotic pathways.
- IGF-1R-siRNA demonstrates significant potential for inducing apoptosis in lung cancer by targeting multiple pathways.
