ΔNp63 promotes IGF1 signalling through IRS1 in squamous cell carcinoma

Abstract

Accumulating evidence has proved that deregulation of ΔNp63 expression plays an oncogenic role in head and neck squamous cell carcinomas (HNSCCs). Besides p63, the type 1-insulin-like growth factor (IGF) signalling pathway has been implicated in HNSCC development and progression. Most insulin/IGF1 signalling converges intracellularly onto the protein adaptor insulin receptor substrate-1 (IRS-1) that transmits signals from the receptor to downstream effectors, including the PI3K/AKT and the MAPK kinase pathways, which, ultimately, promote proliferation, invasion, and cell survival. Here we report that p63 directly controls IRS1 transcription and cellular abundance and fosters the PI3K/AKT and MAPK downstream signalling pathways. Inactivation of ΔNp63 expression indeed reduces tumour cell responsiveness to IGF1 stimulation, and inhibits the growth potential of HNSCC cells. In addition, a positive correlation was observed between p63 and IRS1 expression in human HNSCC tissue arrays and in publicly available gene expression data. Our findings indicate that aberrant expression of ΔNp63 in HNSSC may act as an oncogenic stimulus by altering the IGF signalling pathway.

ΔNp63 in squamous cell carcinoma: defining the oncogenic routes affecting epigenetic landscape and tumour microenvironment

“…A recent report connected ΔNp63 transcriptional activity with the activation of another receptor tyrosine kinase, the insulin growth factor receptor 1 (IGFR-1). In HNSCC cell lines ΔNp63 positively controls the transcription of the adaptor protein Insulin Receptor Substrate 1 (IRS1), an important mediator of the pro-survival and mitogenic signalling of insulin and IGF-1 (Frezza et al, 2018). The modulation of IRS1 levels by ΔNp63 is interesting in light of the role of ΔNp63 in preventing the expression of IGFBP3, which regulate the bioavailability and halflife of circulating IGF-1 (Barbieri et al, 2005).…”

Luteolin-7-O-β-d-Glucoside Inhibits Cellular Energy Production Interacting with HEK2 in Keratinocytes

“…Accordingly, we showed that during keratinocyte differentiation there was a depression of the glucose metabolism (Figure 3C,D). Moreover, ΔNp63 is able to control the insulin receptor substrate (IRS) IRS1 [36], and in our p63RNAi experiments, it also controls IRS4 (Table S1, last row), both of which are responsible of the re-localization of GLUT4 transporter [37] on the plasma membrane, explaining the mechanism of glucose uptake impairment observed during differentiation.…”

Effects of Heshouwuyin on gene expression of the insulin/IGF signalling pathway in rat testis and spermatogenic cells

“…The IRS family includes four isoforms, IRS1-4 (Al-Salam and Irwin 2017;Machado-Neto et al 2018). IRS1 is a mediator of insulin and IGF1, both of which can bind to INSR (Simpson et al 2017;Frezza et al 2018). The PI3K/protein kinase B (also known as Akt) signalling pathway is mediated by IRS2 and plays an important role in cell growth, proliferation, and apoptosis (Lei et al 2018).…”