Function of insulin-like growth factor 1 receptor in cancer resistance to chemotherapy

Abstract

Drug resistance is a primary cause of chemotherapeutic failure; however, how this resistance develops is complex. A comprehensive understanding of chemotherapeutic resistance mechanisms may aid in identifying more effective drugs and improve the survival rates of patients with cancer. Insulin-like growth factor 1 receptor (IGF1R), a member of the insulin receptor family, has been extensively assessed for biological activity, and its putative contribution to tumor cell development and progression. Furthermore, researchers have attended to drugs that target IGF1R since IGF1R functions as a membrane receptor. However, how IGF1R participates in chemotherapeutic resistance remains unclear. Therefore, the present study described the IGF1R gene and its associated signaling pathways, and offered details of IGF1R-induced tumor chemoresistance associated with promoting cell proliferation, inhibition of apoptosis, regulation of ATP-binding cassette transporter proteins and interactions with the extracellular matrix. The present study offered additional explanations for tumor chemotherapy resistance and provided a theoretical basis of IGF1R and its downstream pathways for future possible chemotherapy treatment options.

Keywords: cancer; chemotherapeutic resistance; insulin-like growth factor 1 receptor; mechanisms; review.

Figure 1.

IGF1R signaling pathway and its relevant drug resistance mechanisms: Promoting proliferation, inhibiting apoptosis and inducing changes to ABC transporter proteins and the ECM. Silencing WT1 and mutant p53 causes loss of the inhibitory effects of the IGF1R promoter. Downregulating microRNAs, including miR-143, miR-503, miR-1271, causes the loss of IGF1R mRNA degradation and IGF1R translation inhibitory activity. Serum insulin-like growth factor binding proteins decrease the inhibitory effects of IGF1R post-transcriptionally, increasing IGF1R expression and activity. This may promote downstream phosphatidylinositol 3-kinase/protein kinase B and Grb2/RAS/RAF/mitogen-activated protein kinase signaling cascades, thereby enhancing cell proliferation and anti-apoptotic activity. In addition, IGF1R signaling pathways participate in regulating ABC genes and alter cell responses to chemotherapy. The ECM and IGF1R stabilize and activate the activity of one another. IGF1R, insulin-like growth factor 1 receptor; ABC, ATP-binding cassette; ECM, extracellular matrix; WT1, Wilms tumor 1; miR, microRNA; Grb2, growth factor receptor bound protein 2.