Annexin A6 improves anti-migratory and anti-invasive properties of tyrosine kinase inhibitors in EGFR overexpressing human squamous epithelial cells.

摘要: Annexin A6 (AnxA6), a member of the calcium (Ca2+ ) and membrane binding annexins, is known to stabilize establish formation multifactorial signaling complexes. At plasma membrane, AnxA6 scaffold for protein kinase Cα (PKCα) GTPase-activating p120GAP promote downregulation epidermal growth factor receptor (EGFR) Ras/mitogen-activated (MAPK) signaling. In human squamous A431 epithelial carcinoma cells, which overexpress EGFR, but lack endogenous AnxA6, restoration expression (A431-A6) promotes PKCα-mediated threonine 654 (T654)-EGFR phosphorylation, inhibits EGFR tyrosine activity. This associated with reduced A431-A6 cell growth, also decreased migration invasion in wound healing, matrigel, organotypic matrices. Here, we show that cells display activity vivo, xenograft analysis identifying increased pT654-EGFR levels, phosphorylation compared controls. contrast, PKCα depletion tumors strongly pT654 yet MAPK Moreover, inhibitors (TKIs; gefitinib, erlotinib) more effectively inhibit viability, clonogenic healing Likewise, ability motility invasiveness improves TKI efficacy matrigel assays. correlates greatly surrounding matrix TKI-treated when cultured 3D spheroids. Altogether, these findings implicate elevated levels contribute improve TKI-mediated inhibition migration, invasive properties overexpressing carcinoma.