title: Protein kinase Cα (PKCα) regulates p53 localization and melanoma cell survival downstream of integrin αv in three-dimensional collagen and in vivo.
abstract: 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.
authors: Department of Biosciences and Nutrition, Center for Biosciences, Karolinska Institutet, Huddinge SE-141 83, Sweden.
authors: Stephen D
authors: SD
authors: Smith
authors: Martin
authors: M
authors: Enge
authors: Wenjie
authors: W
authors: Bao
authors: Minna
authors: M
authors: Thullberg
authors: Tânia D F
authors: TD
authors: Costa
authors: Helene
authors: H
authors: Olofsson
authors: Behxhet
authors: B
authors: Gashi
authors: Galina
authors: G
authors: Selivanova
authors: Staffan
authors: S
authors: Strömblad
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D003094:Collagen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039564:Integrin alphaV / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D039564:Integrin alphaV; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003094:Collagen; D051571:Protein Kinase C-alpha