Oncogenic functions of IGF1R and INSR in prostate cancer include enhanced tumor growth, cell migration and angiogenesis

Abstract

We scrutinized the effect of insulin receptor (INSR) in addition to IGF1R in PCa using in vitro and in vivo models. In-vitro overexpression of IGF1R and INSRA, but not INSRB increased cell proliferation, colony formation, migration, invasion and resistance to apoptosis in prostate cancer cells (DU145, LNCaP, PC3). Opposite effects were induced by downregulation of IGF1R and total INSR, but not INSRB. In contrast to tumor cells, non-cancerous epithelial cells of the prostate (EP156T, RWPE-1) were inhibited on overexpression and stimulated by knockdown of receptors. In-vivo analyses using the chicken allantoic membrane assay confirmed the tumorigenic effects of IGF1R and INSR. Apart from promoting tumor growth, IGF1R and INSR overexpression also enhanced angiogenesis indicated by higher vessel density and increased number of desmin-immunoreactive pericytes. Our study underscores the oncogenic impact of IGF1R including significant effects on tumor growth, cell migration, sensitivity to apoptotic/chemotherapeutic agents and angiogenesis, and characterizes the INSR, in particular the isoform INSRA, as additional cancer-promoting receptor in prostate cancer. Both, the insulin-like growth factor receptor 1 and the insulin receptor exert oncogenic functions, thus proposing that both receptors need to be considered in therapeutic settings.

Pro-angiogenic Role of Insulin: From Physiology to Pathology

“…Also, circulating levels of insulin are modulated by several hormones and circulating factors such as amino acids, fatty acids, melatonin, estrogen, leptin, growth hormone, among others (Fu et al, 2013). In mammals, insulin also mediates mitogenic effects in a variety of cell types (Stout, 1991; Qiao et al, 2005; Simó et al, 2006; Shrader et al, 2009; Heidegger et al, 2014). However, other reports have failed to find an insulin-mediated endothelial proliferative response (Liu et al, 2009; Lassance et al, 2013).…”

Mutant p53 potentiates the oncogenic effects of insulin by inhibiting the tumor suppressor DAB2IP

“…High levels of circulating insulin may promote tumor progression by activating the insulin receptor (INSR) and/or insulin-like growth factor 1 (IGF1R) receptor, which is frequently overexpressed in cancer cells (5). In fact, increased INSR/IGF1R activation was linked to accelerated mammary tumor growth in hyperinsulinemic mouse models (6), and IGF1R or INSR overexpression was shown to enhance tumor growth and progression in androgen-independent prostate cancer (7).…”

The insulin-like growth factor (IGF) axis as an anticancer target in prostate cancer

“…In the PCa TRAMP mouse model IGF1 levels are implicated in tumor initiation and progression, whereas the receptors IGFR1 and IGFR2 were found to be downregulated in metastatic lesions [55]. Recently, our group showed both in vitro and in vivo that IGF1R or INSR downregulation significantly reduced tumor growth, colony formation ability, migration and invasion [21].…”

“…However, Table 2 Overview on ongoing or recently finished clinical studies targeting the IGF1R in prostate cancer (July 2015 [15]. Therefore, co-targeting both receptors may be required for sufficient inhibition and anti-tumor efficacy of IGF-based therapies [21,75]. The tyrosine kinase inhibitor insitinib is currently undergoing clinical trial to evaluate the impact of combined IGF1R/INSR inhibition in metastatic CRPC patients.…”

“…Moreover, the IGF axis plays a fundamental role in regulating embryonic growth [19]. IGFs also exert growth stimulating and pro-survival effects on tumor cells and have been shown to mediate carcinogenesis, angiogenesis, malignant cell proliferation and metastatic growth of a variety of tumors [20][21][22].…”