A novel CYR61-triggered 'CYR61-αvβ3 integrin loop' regulates breast cancer cell survival and chemosensitivity through activation of ERK1/ERK2 MAPK signaling pathway

摘要: The angiogenic inducer CYR61 is differentially overexpressed in breast cancer cells exhibiting high levels of Heregulin (HRG), a growth factor closely associated with metastatic phenotype. Here, we examined whether CYR61, independently HRG, actively regulates cell survival and chemosensitivity, the pathways involved. Forced expression HRG-negative MCF-7 notably upregulated its own integrin receptor αvβ3 (>200 times). Small peptidomimetic antagonists dramatically decreased viability CYR61-overexpressing cells, whereas control MCF-7/V remained insensitive. Mechanistically, functional blockade specifically abolished CYR6-induced hyperactivation ERK1/ERK2 MAPK, activation status AKT did not decrease. Moreover, overexpression rendered significantly resistant (>10-fold) to Taxol-induced cytotoxicity. Remarkably, inhibition converted CYR61-induced Taxol-resistant phenotype into hypersensitive one. Thus, augmentation apoptotic death presence demonstrated strong synergism as verified by terminal transferase-mediated dUTP nick-end labeling (TUNEL) assay flow cytometric analysis for DNA content. Indeed, αvβ3, similarly pharmacological MAPK inhibitor U0126, synergistically increased both proportion G2 phase cycle appearance sub-G1 hypodiploid (apoptotic) caused Taxol. Strikingly, impaired accumulation wild-type p53 following Taxol exposure, while or signalings completely restored upregulation p53. antisense downregulation anchorage-independent engineered overexpress their sensitivity Our data provide evidence that sufficient promote proliferation, survival, resistance through αvβ3-activated signaling. identification ‘CYR61-αvβ3 autocrine loop’ epithelial compartment carcinoma strongly suggests targeting may simultaneously prevent angiogenesis, growth, chemoresistance.