Targeting the E3 ligase NEDD4 as a novel therapeutic strategy for IGF1 signal pathway-driven gastric cancer

Abstract

The IGF1 signal pathway is highly activated in some subtype of gastric cancer(GC) that exhibits poor survival and chemotherapy resistance. Although the results of clinical trials of anti-IGF1R monoclonal antibodies and IGF-1R inhibitors have been mostly disappointing in unselected cancer patients, some patients benefit from anti-IGF1R therapy in these failed studies. Therefore, it is necessary to characterize the complex IGF signaling in GC and help refine the strategies targeting the IGF1 pathway. We found that GC cell lines exhibit differential responses to the specific IGF1R inhibitor OSI906. According to the phosphorylation status of Akt upon the OSI906 treatment, we divided the GC cell lines into IGF1R-dependent and IGF1R-independent cells. Both in vitro and in vivo experiments indicate that Dox-induced knockdown of NEDD4 significantly suppresses tumor growth of IGF1R-dependent GC cells and NEDD4 overexpression promotes tumor growth of IGF1R-dependent GC cells. In contrast, the proliferation of IGF1R-independent GC cells is not affected by NEDD4 silencing and overexpression. The rescue experiments show that a PTEN-IRS1 axis is required for NEDD4-mediated regulation of Akt activation and tumor growth in GC cells. Clinically, NEDD4 is expressed higher in IGF1-high GC tissues compared with IGF1-low GC tissues and normal tissues, and the co-high expression of NEDD4 and IGF1 predicts a worse prognosis in GC patients. Taken together, our study demonstrated that NEDD4 specifically promotes proliferation of GC cells dependent on IGF1/IGF1R signaling by antagonizing the protein phosphatase activity of PTEN to IRS1, and targeting NEDD4 may be a promising therapeutic strategy for IGF1 signal pathway-driven gastric cancer.

Evaluating Multiple Metabolic Indicators to Predict Gastric Intestinal Metaplasia Risk

“…This in ammatory environment may contribute to changes in gastric mucosa, as chronic in ammation has been recognized as a precursor to cancer initiation and progression [21]. Both AIP and TyG are indicative of insulin resistance, a key component of MetS, while insulin resistance can lead to hyperinsulinemia and increased levels of insulin-like growth factors, which have been implicated in gastric carcinogenesis [22,23].…”

Targeting SMAD-Dependent Signaling: Considerations in Epithelial and Mesenchymal Solid Tumors

“…Table 2 shows the list of inhibitors targeting ERK, PKC (protein kinase C), PKG (protein kinase G), CK1 (casein kinase 1), protein kinase PAK2, PAK4, and LKB1 (liver kinase B1) [ 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 ]. Others enzyme inhibitors against protein phosphatase, such as (PPM1A/PP2CA, SCP), ubiquitin ligase (NEDD4-2/NEDD4L, HSC70-interacting protein, CHIP, SCFskp1 SCFskp2,) histone acetyltransferase (p300/CREB), and methyltransferase (SET 7/9, SETDB1/ESET, m6 methyltransferase, PRAP1), are listed in Table 2 [ 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , …”

NEDD4 and NEDD4L: Ubiquitin Ligases Closely Related to Digestive Diseases

“…Ke Wang et al found that NEDD4 overexpression promoted tumor proliferation in insulin-like growth factor 1 receptor (IGF1R)-dependent GC cells, and therefore hypothesized that NEDD4 specifically promotes the growth of GC cells that are dependent on the IGF1/IGF1R signaling pathway by antagonizing the protein phosphatase activity of IRS 1 by antagonizing PTEN. Thus, NEDD4 may be one of the therapeutic targets for the treatment of GC driven by the IGF 1 signaling pathway [83,84]. Recently, Liang Xu et al reported that the expression of inhibin 2 (PHB 2) in GC tissues was significantly higher than in normal tissues adjacent to the cancer and was associated with poor clinical prognosis.…”

“…This unveils a new target for the treatment of CRC [94] (p. 21). Recently, Ying-Nan Wang et al cultured CRC cells with cholesterol-lowering agents and lipoprotein-free medium, and found that SR10 [84], a RAR-related orphan receptor α/γ (RORα/γ) agonist, could activate the transcription of NEDD4 by binding to the promoter of the NEDD4 gene, thus promoting the ubiquitylation and degradation of c-myc and inhibiting the proliferation and metastasis of CRC cells. Moreover, atorvastatin combined with ROR α/γ agonists was found to have a synergistic effect in inhibiting the proliferation and migration of CRC cells, which provides a new strategy for CRC therapy by inhibiting the cholesterol-ROR α/γ-c-myc axis [91].…”