Targeting Insulin-Like Growth Factor 1 Receptor Inhibits Pancreatic Cancer Growth and Metastasis

Abstract

Pancreatic cancer is one of the most lethal cancers. Increasing incidence and mortality indicates that there is still much lacking in detection and management of the disease. This is partly due to a lack of specific symptoms during early stages of the disease. Several growth factor receptors have been associated with pancreatic cancer. Here, we have investigated if an RNA interference approach targeted to IGF-IR could be effective and efficient against pancreatic cancer growth and metastasis. For that, we evaluated the effects of IGF-1R inhibition using small interfering RNA (siRNAs) on tumor growth and metastasis in HPAC and PANC-1 pancreatic cancer cell lines. We found that silencing IGF-1R inhibits pancreatic cancer growth and metastasis by blocking key signaling pathways such AKT/PI3K, MAPK, JAK/STAT and EMT. Silencing IGF-1R resulted in an anti-proliferative effect in PANC-1 and HPAC pancreatic cancer cell lines. Matrigel invasion, transwell migration and wound healing assays also revealed a role for IGF-1R in metastatic properties of pancreatic cancer. These results were further confirmed using Western blotting analysis of key intermediates involved in proliferation, epithelial mesenchymal transition, migration, and invasion. In addition, soft agar assays showed that silencing IGF-1R also blocks the colony forming capabilities of pancreatic cancer cells in vitro. Western blots, as well as, flow cytometric analysis revealed the induction of apoptosis in IGF-1R silenced cells. Interestingly, silencing IGF-1R also suppressed the expression of insulin receptor β. All these effects together significantly control pancreatic cancer cell growth and metastasis. To conclude, our results demonstrate the significance of IGF-1R in pancreatic cancer.

IGFBP2 Activates the NF-κB Pathway to Drive Epithelial–Mesenchymal Transition and Invasive Character in Pancreatic Ductal Adenocarcinoma

“…The insulin-like growth factor (IGF) system has recently been implicated in the progression of PDAC (7). IGF-binding protein 2 (IGFBP2) is one of six proteins in the IGFBP family that bind IGFs with high affinity (8).…”

Co-Targeting IGF-1R and Autophagy Enhances the Effects of Cell Growth Suppression and Apoptosis Induced by the IGF-1R Inhibitor NVP-AEW541 in Triple-Negative Breast Cancer Cells

“…Insulin-like growth factor-1 (IGF-1) signaling is associated with various types of cancers, including pancreatic, lung and breast cancers [13–15]. Activation of IGF-1 receptor (IGF-1R) by IGF-1 binding results in cell proliferation, metastasis and drug resistance, and it is reported that IGF-1R promotes survival and proliferation of TNBC cell lines [16].…”

Analysis of Important Gene Ontology Terms and Biological Pathways Related to Pancreatic Cancer

“…Some of such regulatory factors have also been contained in our results. MAPK signaling pathway ( hsa04010 ) has been confirmed to have crosstalk with mTOR signaling pathway as we have mentioned above and has been reported to be quite crucial for the invasion and metastasis of pancreatic cancer [80, 81]. Apart from such two functional signaling pathways, another pathway, which has been widely reported to contribute to endometrial cancer, ERBB signaling pathway ( hsa04012 ), is also in Table 1 [82].…”