Ablation of insulin receptor substrates 1 and 2 suppresses Kras -driven lung tumorigenesis

Abstract

Non-small-cell lung cancer (NSCLC) is a leading cause of cancer death worldwide, with 25% of cases harboring oncogenic Kirsten rat sarcoma (). Although KRAS direct binding to and activation of PI3K is required for -driven lung tumorigenesis, the contribution of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in the context of mutant remains controversial. Here, we provide genetic evidence that lung-specific dual ablation of insulin receptor substrates 1/2 (/), which mediate insulin and IGF1 signaling, strongly suppresses tumor initiation and dramatically extends the survival of a mouse model of lung cancer with activation and loss. Mice with / loss eventually succumb to tumor burden, with tumor cells displaying suppressed Akt activation and strikingly diminished intracellular levels of essential amino acids. Acute loss of / or inhibition of IR/IGF1R in -mutant human NSCLC cells decreases the uptake and lowers the intracellular levels of amino acids, while enhancing basal autophagy and sensitivity to autophagy and proteasome inhibitors. These findings demonstrate that insulin/IGF1 signaling is required for-mutant lung cancer initiation, and identify decreased amino acid levels as a metabolic vulnerability in tumor cells with IR/IGF1R inhibition. Consequently, combinatorial targeting of IR/IGF1R with autophagy or proteasome inhibitors may represent an effective therapeutic strategy in -mutant NSCLC.

Insulin promotes invasion and migration of KRASG12D mutant HPNE cells by upregulating MMP‐2 gelatinolytic activity via ERK‐ and PI3K‐dependent signalling

“…4 Numerous studies have focused on the role of KRAS mutation in promoting tumorigenesis. 42 Therefore, KRAS mutation is essential for the occurrence of PDAC via increasing architecture and cytological atypia. 40 Oncogenic KRAS G12D can continuously activate its downstream pathways, F I G U R E 6 Effect of insulin on the activity of PI3K/AKT and MAPK signalling in HPNE and HPNE-mut-KRAS cells.…”

“…15 In addition, the relationship between insulin and KRAS mutation has also been studied in lung cancer and it is reported that insulin/IGF1 signalling is important for lung cancer initiation after KRAS mutation. 42 Therefore, KRAS mutation is essential for the occurrence of PDAC via increasing architecture and cytological atypia.…”

Insulin Receptor Isoforms in Cancer

“…In addition, 11% of the NSCLC specimens expressed only the IR-A isoform [ 43 ]. Moreover, in a strongly oncogenic mouse model (K-Ras activation and p53 loss) the inhibition of the IR signaling pathway, through the block of IRS-1 and IRS-2, suppressed cancer initiation in lung cells and improved the mouse survival [ 52 ]. Finally, in non-small cell lung cancer cell IR-knock down caused a strong induction of pro-apoptotic cytokines (IL-20, TNF-α), suggesting a role of IR in tumor cell survival via suppression of pro-apoptotic cytokines [ 53 ].…”

Silencing of NAMPT leads to up-regulation of insulin receptor substrate 1 gene expression in U87 glioma cells

“…As shown in Figure 7, inducible effect of NAMPT silencing on the expression of gene encoding insulin receptor substrate 1, which can interact with insulin receptor and insulin-like growth factor receptors and mediate the control of various cellular processes by insulin as well as insulin-like growth factors (Xu et al 2018;Sun et al 2019;Wu et al 2019), is not correlated well with suppression of cell proliferation of glioma cells, but a strong up-regulation of IGFBP3, which has anti-proliferative properties (Yan et al 2017;Fan et al 2018;Zhou et al 2018;Tu et al 2019), and possibly contributes to the anti-proliferative effect of NAMPT silencing. IGFBP3 is a pleiotropic protein, which plays an important role in the regulation of the insulin-like growth factors and has additional functions independent on IGFs (Ingermann et al 2010;Nedic et al 2013;Canel et al 2017;Wang et al 2017).…”

“…Among others, insulin-like growth factor binding protein 3 (IGFBP3), hexokinase 2 (HK2), period circadian regulator 2 (PER2), clusterin (CLU), BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), tumor protein D52 (TPD52), growth arrest and DNA-damage-inducible, alpha (GADD45A), and marker of proliferation Ki-67 (MKI67) have been studied. These polyfunctional proteins play an important role in the regulation of metabolism, cell proliferation, surviving and apoptosis and biological clock (Fan et al 2018;Liu et al 2018;Qu et al 2018;Xiong et al 2018;Xu et al 2018;Zhou et al 2018;Chen et al 2014Chen et al , 2019Niu et al 2019;Li et al 2019;Wu et al 2019).…”