Protein kinase C? (PKC?) regulates p53 localization and melanoma cell survival downstream of integrin ?v in three-dimensional collagen and in vivo.

ABSTRACT: Protein kinase C ? (PKC?) is overexpressed in numerous types of cancer. Importantly, PKC? has been linked to metastasis of malignant melanoma in patients. However, it has been unclear how PKC? may be regulated and how it exerts its role in melanoma. Here, we identified a role for PKC? 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 ?v-mediated up-regulation of PKC? and PKC?-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 ?v, which acts to suppress p53 activity. Interestingly, microarray analysis revealed that PKC? was up-regulated by integrin ?v in a three-dimensional microenvironment-dependent manner. Integrin ?v 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 PKC? inhibited the integrin ?v-mediated relocalization of p53. Importantly, knockdown of PKC? also promoted apoptosis in three-dimensional collagen and in vivo, resulting in reduced tumor growth. This indicates that PKC? constitutes a crucial component of the integrin ?v-mediated pathway(s) that promote p53 relocalization and melanoma survival.

SUBMITTER: Smith SD 

PROVIDER: S-EPMC3436133 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature