Redox regulation of anoikis resistance of metastatic prostate cancer cells: key role for Src and EGFR-mediated pro-survival signals

Abstract

Resistance to detachment-induced apoptosis, a process commonly referred as anoikis, is emerging as a hallmark of metastatic malignancies, mainly because it can ensure anchorage-independent growth and survival during organ colonization. Besides, a sustained oxidative stress has been associated with several steps of carcinogenesis, including transformation and achievement of a motile mesenchymal phenotype. Here, we demonstrate that metastatic prostate carcinoma cells, undergoing a constitutive deregulated production of reactive oxygen species due to sustained activation of 5-lipoxygenase, lack suicidal pathways in response to lack of matrix contact. These amplified and persistent redox signals in PC3 cells leads to maintenance of Src oxidation and activation in the absence of adhesion, thereby sustaining a ligand-independent phosphorylation of epidermal growth factor receptor. This leads to chronic activation of pro-survival signals, culminating in degradation of the pro-apoptotic protein Bim, thereby promoting cell survival even in the absence of proper adhesion. Anoikis sensitivity of metastatic cells is restored with antioxidant intervention or genetic manipulation of the redox-mediated pro-survival pathway, as well as exposure to a pro-oxidant environment strongly increases anoikis resistance in non-transformed prostate epithelial cells. Hence, our results allow new insight into the aetiology of the molecular mechanisms granting anoikis resistance of metastatic cancers, opening new avenues to pharmacological intervention for antioxidant-sensitive invasive tumours.