Integrin [alpha]v-mediated inactivation of p53 controls a MEK1-dependent melanoma cell survival pathway in three-dimensional collagen

Integrin [alpha]v is required for melanoma cell survival and tumor growth in various models. To elucidate integrin [alpha]v-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 [alpha]v inactivated p53 and that suppression of p53 activity by dominant negative p53 or p53-small interfering RNA obviated the need for integrin [alpha]v for melanoma cell survival in 3D-collagen and for tumor growth in vivo. This indicates that integrin [alpha]v-mediated inactivation of p53 functionally controls melanoma cell survival. Furthermore, we found that melanoma cell integrin [alpha]v was required for MAPK 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 [alpha]v-negative melanoma cells by suppression of p53, whereas concomitant block of MEK1 induced apoptosis. This suggests that integrin [alpha]v controls melanoma cell survival in 3D-collagen through a pathway involving p53 regulation of MEK1 signaling.