Integrin αv-mediated inactivation of p53 controls a MEK1-dependent melanoma cell survival pathway in three-dimensional collagen

Abstract

Integrin αv is required for melanoma cell survival and tumor growth in various models. To elucidate integrin αv-mediated melanoma cell survival mechanisms, we used a three-dimensional (3D) collagen gel model mimicking the pathophysiological microenvironment of malignant melanoma in the dermis. We found that integrin αv inactivated p53 and that suppression of p53 activity by dominant negative p53 or p53-small interfering RNA obviated the need for integrin αv for melanoma cell survival in 3D-collagen and for tumor growth in vivo. This indicates that integrin αv-mediated inactivation of p53 functionally controls melanoma cell survival. Furthermore, we found that melanoma cell integrin αv was required for MARK kinase (MEK) 1 and extracellular signal-regulated kinase (ERK) 1/2 activity in 3D-collagen, whereas inhibition of MEK1 activity induced apoptosis. Surprisingly, MEK1 and ERK1/2 activities were restored in integrin αv-negative melanoma cells by suppression of p53, whereas concomitant block of MEK1 induced apoptosis. This suggests that integrin αv controls melanoma cell survival in 3D-collagen through a pathway involving p53 regulation of MEK1 signaling.