Abstract
Insulin-like growth factor (IGF) signaling pathway is an important regulatory mechanism of tumorigenesis and drug resistance in many cancers. The present study explored the potential synergistic effects between IGF receptor (IGFR) inhibition and other molecular targeted agents (MTA) in HCC cells. HCC cell lines (Hep3B, PLC5, and SK-Hep1) and HUVECs were tested. The MTA tested included sorafenib, sunitinib, and the IGFR kinase inhibitor NVP-AEW541. The potential synergistic antitumor effects were tested by median dose effect analysis and apoptosis assay in vitro and by xenograft models in vivo. The activity and functional significance of pertinent signaling pathways and expression of apoptosis-related proteins were measured by RNA interference and Western blotting. We found that IGF can activate IGFR and downstream AKT signaling activities in all the HCC cells tested, but the growth-stimulating effect of IGF was most prominent in Hep3B cells. NVP-AEW541 can abrogate IGF-induced activation of IGFR and AKT signaling in HCC cells. IGF can increase the resistance of HCC cells to sunitinib. The apoptosis-inducing effects of sunitinib, but not sorafenib, were enhanced when IGFR signaling activity was inhibited by NVP-AEW541 or IGFR knockdown. Chk2 kinase activation was found contributory to the synergistic anti-tumor effects between sunitinib and IGFR inhibition. Our data indicate that the apoptosis-potentiating effects of IGFR inhibition for HCC may be drug-specific. Combination therapy of IGFR inhibitors with other MTA may improve the therapeutic efficacy in HCC.
Highlights
Molecular targeted therapy, which aims at specific molecular derangements in cancer cells or their microenvironment, is currently standard treatment for patients with advanced hepatocellular carcinoma (HCC) [1]
The growth-inhibitory effects of the IGF receptor (IGFR) inhibitor NVPAEW541 on HCC cells and human umbilical venous endothelial cells (HUVEC) were determined by MTT assay
The small-molecule IGFR inhibitor NVPAEW541 can enhance apoptosis of HCC cells induced by selected molecular targeted agents (MTA), such as sunitinib
Summary
Molecular targeted therapy, which aims at specific molecular derangements in cancer cells or their microenvironment, is currently standard treatment for patients with advanced hepatocellular carcinoma (HCC) [1]. The insulin-like growth factor (IGF) signaling pathway plays important roles in HCC tumorigenesis [6,7]. Upregulation of IGF and IGFR may be induced by hepatitis B virus x protein [12,13] and p53mt249 [14], a gain-of function mutant of p53 that is associated with HCC and aflatoxin B1 exposure. This suggested that IGF signaling is closely associated with other tumorigenic processes of HCC and may serve as a therapeutic target
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