Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine kinases, which can be further classified into three PKC isozymes subfamilies: conventional or classic, novel or nonclassic, and atypical. PKC isozymes are known to be involved in cell proliferation, survival, invasion, migration, apoptosis, angiogenesis, and drug resistance. Because of their key roles in cell signaling, PKC isozymes also have the potential to be promising therapeutic targets for several diseases, such as cardiovascular diseases, immune and inflammatory diseases, neurological diseases, metabolic disorders, and multiple types of cancer. This review primarily focuses on the activation, mechanism, and function of PKC isozymes during cancer development and progression.

https://downloads.hindawi.com/archive/2014/231418.pdf

Protein Kinase C (PKC) Isozymes and Cancer

Anaplastic cancer constitutes 1% of thyroid cancers, and it is one of the most aggressive cancers Treatment options are external radiation therapy and/or chemotherapy The success rate with these treatment modalities is not satisfactory We aimed to evaluate the effects of metformin (MET) and pioglitazone (PIO) combination on apoptosis and AMP-activated protein kinase/mammalian target of rapamycin (mTOR) signaling pathway in human anaplastic thyroid cancer cells In this study, we evaluated the effects of MET and PIO individually and the combination of the two drugs on the cellular lines SW1736 and C643 ATC Genes contained in the mTOR signaling pathway were examined using human mTOR Signalization RT2 Profiler PCR Array In C643 and SW1736 cell lines, IC50 doses of MET and PIO were found out as 1769 mM, 1164 mM, 2712 µM, and 2317 µM Also, the combination of MET and PIO was determined as an additive according to isobologram analyses We have found the downregulation of the expression levels of oncogenic genes: AKT3, CHUK, CDC42, EIF4E, HIF1A, IKBKB, ILK, MTOR, PIK3CA, PIK3CG, PLD1, PRKCA, and RICTOR genes, in the MET and PIO combination-treated cells In addition, expression levels of tumor suppressor genes, DDIT4, DDIT4L, EIF4EBP1, EIF4EBP2, FKBP1A, FKBP8, GSK3B, MYO1C, PTEN, ULK1, and ULK2, were found to have increased significantly The MET + PIO combination was first applied to thyroid cancer cells, and significant reductions in the level of oncogenic genes were detected The decreases, particularly, in AKT3, DEPTOR, EIF4E, ILK, MTOR, PIK3C, and PRKCA expressions indicate that progression can be prevented in thyroid cancer cells and these genes could be selected as therapeutic targets

Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cells

Targeting protein kinase C in sarcoma

Simple Summary Protein kinase C (PKC) isozymes play key roles in the proliferation, differentiation, survival, migration, invasion, apoptosis, and anticancer drug resistance of cancer cells. PKC isozymes are attractive therapeutic targets for cancer and have great potential as diagnostic and prognostic biomarkers for diagnosing cancers and for predicting disease-free survival and survival rates, respectively. This review discusses the potential of PKC isozymes as diagnostic and prognostic biomarkers and therapeutic targets for cancer. Abstract Protein kinase C (PKC) is a large family of calcium- and phospholipid-dependent serine/threonine kinases that consists of at least 11 isozymes. Based on their structural characteristics and mode of activation, the PKC family is classified into three subfamilies: conventional or classic (cPKCs; α, βI, βII, and γ), novel or non-classic (nPKCs; δ, ε, η, and θ), and atypical (aPKCs; ζ, ι, and λ) (PKCλ is the mouse homolog of PKCι) PKC isozymes. PKC isozymes play important roles in proliferation, differentiation, survival, migration, invasion, apoptosis, and anticancer drug resistance in cancer cells. Several studies have shown a positive relationship between PKC isozymes and poor disease-free survival, poor survival following anticancer drug treatment, and increased recurrence. Furthermore, a higher level of PKC activation has been reported in cancer tissues compared to that in normal tissues. These data suggest that PKC isozymes represent potential diagnostic and prognostic biomarkers and therapeutic targets for cancer. This review summarizes the current knowledge and discusses the potential of PKC isozymes as biomarkers in the diagnosis, prognosis, and treatment of cancers.

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Protein Kinase C (PKC) Isozymes as Diagnostic and Prognostic Biomarkers and Therapeutic Targets for Cancer

A point mutation of protein kinase Calpha (PKCalpha) has been described in pituitary adenomas and in follicular adenomas and thyroid carcinomas. The mutation results in an exchange of aspartic acid into a glycine of the amino acid 294 of PKCalpha, which is located adjacent to the Ca (2+)-binding hinge region and has been proposed as an activation inhibitor. To investigate its biochemical sequelae, we constructed the mutated enzyme and expressed it in human embryonic kidney cells (HEK). The K M of the purified enzyme for Ca (2+) and its K M for the substrate MBP 4 - 14 was not altered by the mutation. Translocation of PKCalpha to HEK cell membranes upon activation was not changed and the mutant potently inhibited cell proliferation upon 5-fold stable overexpression in HEK cells. Thus, loss of function in mutated PKCalpha was excluded. A screen for the mutation using a restriction assay with a sensitivity of at least 8 % for the mutated DNA did not show any mutation in 11 carcinoma and 13 adenomatous thyroid samples. We conclude that the A294G mutation of PKCalpha does not detectably affect its biochemical properties in vitro or in vivo, and is at least rare in thyroid neoplasias, in Germany.

Effects of the putatively oncogenic protein kinase Calpha D294G mutation on enzymatic activity and cell growth and its occurrence in human thyroid neoplasias.

P. Goretzki

Papers

Effects of the putatively oncogenic protein kinase Calpha D294G mutation on enzymatic activity and cell growth and its occurrence in human thyroid neoplasias.