Protein kinase C α (PKCα) is overexpressed in numerous types of
cancer. Importantly, PKCα has been linked to
metastasis of
malignant melanoma in patients. However, it has been unclear how PKCα may be regulated and how it exerts its role in
melanoma. Here, we identified a role for PKCα in
melanoma cell survival in a three-dimensional
collagen model mimicking the in vivo pathophysiology of the dermis. A pathway was identified that involved
integrin αv-mediated up-regulation of PKCα and PKCα-dependent regulation of p53 localization, which was connected to
melanoma cell survival.
Melanoma survival and growth in three-dimensional microenvironments requires the expression of
integrin αv, which acts to suppress p53 activity. Interestingly, microarray analysis revealed that PKCα was up-regulated by
integrin αv in a three-dimensional microenvironment-dependent manner.
Integrin αv was observed to promote a relocalization of endogenous p53 from the nucleus to the cytoplasm upon growth in three-dimensional
collagen as well as in vivo, whereas stable knockdown of PKCα inhibited the
integrin αv-mediated relocalization of p53. Importantly, knockdown of PKCα also promoted apoptosis in three-dimensional
collagen and in vivo, resulting in reduced
tumor growth. This indicates that PKCα constitutes a crucial component of the
integrin αv-mediated pathway(s) that promote p53 relocalization and
melanoma survival.