ADAM17-siRNA inhibits MCF-7 breast cancer through EGFR-PI3K-AKT activation

Abstract

A disintegrin and metalloproteinase-17 (ADAM17) can cut and release a wide variety of epidermal growth factor receptor (EGFR) ligands to promote survival, invasion and proliferation of cancer cell, and therefore, is considered to be a potential therapeutic target for cancer. The main goal of the present study was to observe the effects of ADAM17 small interfering RNA (ADAM17-siRNA) on human MCF-7 breast cancer and investigate its activation pathway. In vitro, MCF-7 cells were divided into ADAM17-siRNA groups, nonsense siRNA groups, AG1478 (selective EGFR blocker) groups, LY294002 [phosphatidylinositol 3-kinase (PI3K) phosphorylation inhibitor] groups, PD0325901 [mitogen extracellular kinase (MEK) inhibitor] groups and control groups. In vivo, MCF-7 cells were implanted subcutaneously into nude mice and then these mice were randomly divided into ADAM17-siRNA groups, vector groups and control groups. Our data showed that compared with the control groups, ADAM17-siRNA, AG1478 and LY294002 could inhibit the migration and proliferation of MCF-7 cells, but PD0325901 and nonsense siRNA did not show this effect. Except that specific ADAM17-siRNA could inhibit the expression of ADAM17 mRNA, others did not change it. Western blot analysis further confirmed that EGFR-PI3K-AKT signaling pathway is involved in ADAM17-siRNA inhibiting migration and proliferation of MCF-7 cells. Similarly to the former, the growth of MCF-7 breast cancer in nude mice was significantly inhibited by ADAM17-siRNA. Compared with the control group and the vector group, the tumor volume was smaller in the ADAM17-siRNA group, the tissues developed large areas of necrosis, immunohistochemistry showed low expressions of ADAM17 and Ki-67 and western blot analysis proved that the expression of ADAM17 protein in the tissue was also reduced. The present study suggests that ADAM17-siRNA inhibits MCF-7 breast cancer and is activated through the EGFR-PI3K-AKT signaling pathway.

A cancer pharmacogenomic screen powering crowd-sourced advancement of drug combination prediction

“…Synergy observed between ADAM17 and PI3K/AKT pathway inhibitors may work through independent inhibition of multiple cancer hallmarks, or via a more direct mechanism whereby inhibition of ADAM17 driven proteolysis and shedding of RTKs 18 stabilizes and increases signaling through PI3K/AKT 37,38 . Notably ADAM17 predominantly influences RTK's other than EGFR/ERBB2 18 , and no benefit is seen in cells with mutations in these genes.…”

Metastatic triple-negative breast cancer patient with TP53 tumor mutation experienced 11 months progression-free survival on bortezomib monotherapy without adverse events after ending standard treatments with grade 3 adverse events

“…The enzyme encoded by ADAM17, also known as tumor necrosis factor-α-converting enzyme (TACE) sheds the extracellular domain of various receptors such as heparin-binding EGF, transforming growth factor-α (TGFA), amphiregulin (AREG), neuregulin (NRG), epiregulin (EREG), and β-cellulin (BTC) (Meng et al 2016) from the cell membrane leading to an activation of downstream signaling pathways with significance in triple-negative breast cancer cells (Caiazza et al 2015). NOTCH3 is a reported breast cancer driver gene where inactivating mutations or deletions in the PEST domain activate the Notch pathway (Wang et al 2015).…”

MEK inhibitor, PD98059, promotes breast cancer cell migration by inducing β-catenin nuclear accumulation

“…It has been shown that the activation of EGFR signaling stimulates β-catenin nuclear translocation and contributes to the acquisition of a motile phenotype by upregulating the expression of MMPs (13,42). Although MCF-7 and MDA-MB-231 are cell lines with two totally different genetic backgrounds, EGFR is expressed in these cells (43,44). Therefore, it is not surprising that β-catenin nuclear translocation induced by PD98059 depends on the activation of EGFR in these breast cancer cell lines.…”