Functional alterations in protein kinase C beta II expression in melanoma.
Protein kinase C (PKC) is a heterogeneous family of serine/threonine protein kinases that have different biological effects in normal and neoplastic melanocytes (MCs). To explore the mechanism behind their differential response to PKC activation, we analyzed the expression profile of all nine PKC isoforms in normal human MCs, HPV16 E6/E7 immortalized MCs, and a panel of melanoma cell lines. We found reduced PKCbeta and increased PKCzeta and PKCiota expression at both the protein and mRNA levels in immortalized MCs and melanoma lines. We focused on PKCbeta as it has been functionally linked to melanin production and oxidative stress response. Re-expression of PKCbeta in melanoma cells inhibited colony formation in soft agar, indicating that PKCbeta loss in melanoma is important for melanoma growth. PKCbetaII, but not PKCbetaI, was localized to the mitochondria, and inhibition of PKCbeta significantly reduced UV-induced reactive oxygen species (ROS) in MCs with high PKCbeta expression. Thus alterations in PKCbeta expression in melanoma contribute to their neoplastic phenotype, possibly by reducing oxidative stress, and may constitute a selective therapeutic target.
Voris
John P
JP
The Oncology Institute, Loyola University Chicago, Maywood, IL, USA.
Sitailo
Leonid A
LA
Rahn
Heidi R
HR
Defnet
Ann
A
Gerds
Aaron T
AT
Sprague
Robert
R
Yadav
Vipin
V
Caroline Le Poole
I
I
Denning
Mitchell F
MF
D002460:Cell Line; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008544:Melanocytes / Q000201:enzymology / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010641:Phenotype; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D064546:Protein Kinase C beta; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D017382:Reactive Oxygen Species; D011493:Protein Kinase C; D064546:Protein Kinase C beta