The
protein kinase C (PKC) family, the most prominent target of
tumor-promoting
phorbol esters, is functionally linked to cell differentiation, growth, survival, migration and
tumorigenesis and so mediates
tumor cell proliferation, survival, multidrug resistance, invasion,
metastasis and
tumor angiogenesis. Therefore, targeting PKC
isozymes may represent an attractive target for novel anticancer
therapies. Recent preclinical and clinical studies using the macrocyclic
bisindolylmaleimide enzastaurin or the N-benzylstaurosporine
midostaurin demonstrate promising activity of PKC inhibitors in a variety of
tumors, including
diffuse large B-cell lymphoma,
multiple myeloma and Waldenstroem's
macroglobulinemia. However, our knowledge of
PKCs in
tumorigenesis is still only partial and each PKC
isoform may contribute to
tumorigenesis in a distinct way. Specifically, PKC
isoforms have vastly different roles, which vary depending on expression levels of organ and tissue distribution, cell type, intracellular localization,
protein-
protein and
lipid-
protein interactions and the
biologic environment. Although PKC activation generally positively affects
tumor cell growth, motility, invasion and
metastasis, recent reports show that many
PKCs can also have negative effects. Therefore, it is necessary to further dissect the relative contribution of PKC
isozymes in the development and progression of specific
tumors in order to identify therapeutic opportunities, using either PKC inhibitors or PKC activators.