BACKGROUND: Obesity is a risk factor for endometrial cancer (EC). However, it is not known how insulin receptor isoform A (IR-A) and insulin-like growth factor 1 receptor (IGF-1R), cognate receptors for insulin and IGFs, respectively, regulate malignant behaviors of EC. In this study, we examined the biological effects of IR-A/IGF-1R, explored the downstream signaling cascades, and assessed the therapeutic potential of targeting IR-A/IGF-1R in vivo. METHODS: The expression levels of IR-A and IGF-1R were examined by qRT-PCR and Western blotting. Upon down-regulating IR-A and/or IGF-1R by sh-IR-A and/or sh-IGF-1R, respectively, cell migration, invasion, apoptosis, and epithelial-mesenchymal transition (EMT) were examined by wound healing, transwell invasion, flow cytometry, and Western blotting, respectively. Furthermore, the effect of sh-IR-A and/or sh-IGF-1R on phosphatidylinositide 3-kinases (PI3K)/AKT and ERK pathways was measured by Western blotting. Lastly, we monitored xenograft growth and EMT in vivo. RESULTS: Both IR-A and IGF-1R were significantly up-regulated in EC cells. Knockdown of IR-A or IGF-1R alone was sufficient to reduce migration and invasion, enhance apoptosis, and inhibit EMT of EC cells, and the most significant alterations were observed in cells co-transfected with sh-IR-A+ sh-IGF-1R. These phenotypes were associated with inactivating PI3K/AKT and ERK signaling by sh-IR-A and/or sh-IGF-1R. Consistent with in vitro findings, sh-IR-A or sh-IGF-1R significantly inhibited xenograft growth and EMT in vivo. CONCLUSION: IR-A and IGF-1R-mediated signals, by activating PI3K/AKT and ERK pathways, can induce multiple malignant phenotypes of EC cells. Therefore, targeting IR-A or IGF-1R may provide therapeutic benefits for EC.
BACKGROUND: Obesity is a risk factor for endometrial cancer (EC). However, it is not known how insulin receptor isoform A (IR-A) and insulin-like growth factor 1 receptor (IGF-1R), cognate receptors for insulin and IGFs, respectively, regulate malignant behaviors of EC. In this study, we examined the biological effects of IR-A/IGF-1R, explored the downstream signaling cascades, and assessed the therapeutic potential of targeting IR-A/IGF-1R in vivo. METHODS: The expression levels of IR-A and IGF-1R were examined by qRT-PCR and Western blotting. Upon down-regulating IR-A and/or IGF-1R by sh-IR-A and/or sh-IGF-1R, respectively, cell migration, invasion, apoptosis, and epithelial-mesenchymal transition (EMT) were examined by wound healing, transwell invasion, flow cytometry, and Western blotting, respectively. Furthermore, the effect of sh-IR-A and/or sh-IGF-1R on phosphatidylinositide 3-kinases (PI3K)/AKT and ERK pathways was measured by Western blotting. Lastly, we monitored xenograft growth and EMT in vivo. RESULTS: Both IR-A and IGF-1R were significantly up-regulated in EC cells. Knockdown of IR-A or IGF-1R alone was sufficient to reduce migration and invasion, enhance apoptosis, and inhibit EMT of EC cells, and the most significant alterations were observed in cells co-transfected with sh-IR-A+ sh-IGF-1R. These phenotypes were associated with inactivating PI3K/AKT and ERK signaling by sh-IR-A and/or sh-IGF-1R. Consistent with in vitro findings, sh-IR-A or sh-IGF-1R significantly inhibited xenograft growth and EMT in vivo. CONCLUSION: IR-A and IGF-1R-mediated signals, by activating PI3K/AKT and ERK pathways, can induce multiple malignant phenotypes of EC cells. Therefore, targeting IR-A or IGF-1R may provide therapeutic benefits for EC.
Authors: Adrian V Hernandez; Vinay Pasupuleti; Vicente A Benites-Zapata; Priyaleela Thota; Abhishek Deshpande; Faustino R Perez-Lopez Journal: Eur J Cancer Date: 2015-11-18 Impact factor: 9.162
Authors: A Ullrich; A Gray; A W Tam; T Yang-Feng; M Tsubokawa; C Collins; W Henzel; T Le Bon; S Kathuria; E Chen Journal: EMBO J Date: 1986-10 Impact factor: 11.598