Protein Kinase C alpha (PKC alpha) Regulates p53 Localization and Melanoma Cell Survival Downstream of Integrin alpha v in Three-dimensional Collagen and in Vivo

作者：Smith Stephen D; Enge Martin; Bao Wenjie; Thullberg Minna; Costa Tania D F; Olofsson Helene; Gashi Behxhet; Selivanova Galina; Stromblad Staffan^*

来源：Journal of Biological Chemistry, 2012, 287(35): 29336-29347.

DOI：10.1074/jbc.M112.341917

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

• 出版日期2012-8-24