Protein Kinase C Epsilon Is a Key Regulator of Mitochondrial Redox Homeostasis in Acute Myeloid Leukemia

Abstract Ingenol 3-angelate (PEP005) is a selective small molecule activator of protein kinase C (PKC) extracted from the plant Euphorbia peplus, whose sap has been used as a traditional medicine for the treatment of skin conditions including warts and cancer. We report here that PEP005 also has potent antileukemic effects, inducing apoptosis in myeloid leukemia cell lines and primary acute myeloid leukemia (AML) cells at nanomolar concentrations. Of importance, PEP005 did not induce apoptosis in normal CD34+ cord blood myeloblasts at up to 2-log concentrations higher than those required to induce cell death in primary AML cells. The effects of PEP005 were PKC dependent, and PEP005 efficacy correlated with expression of PKC-delta. The delta isoform of PKC plays a key role in apoptosis and is therefore a rational potential target for antileukemic therapies. Transfection of KG1a leukemia cells, which did not express PKC-delta or respond to PEP005, with enhanced green fluorescent protein (EGFP)-PKC-delta restored sensitivity to induction of apoptosis by PEP005. Our data therefore suggest that activation of PKC-delta provides a novel approach for treatment of acute myeloid leukemia and that screening for PKC-delta expression may identify patients for potential responsiveness to PEP005. (Blood. 2005;106:1362-1368)

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Synergistic effect of all-trans retinoic acid in combination with protein kinase C 412 in FMS-like tyrosine kinase 3-mutated acute myeloid leukemia cells

Molecular Medicine Reports ◽

10.3892/mmr.2015.3203 ◽

2015 ◽

Vol 11 (5) ◽

pp. 3969-3975 ◽

Cited By ~ 6

Author(s):

HOANG THANH CHI ◽

BUI THI KIM LY ◽

HOANG ANH VU ◽

YUKO SATO ◽

PHU CHI DUNG ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Protein Kinase C ◽

Retinoic Acid ◽

Myeloid Leukemia ◽

Leukemia Cells ◽

Kinase C ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Acute Myeloid Leukemia Cells ◽

Acute Myeloid

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Faculty Opinions recommendation of Protein kinase C epsilon modulates nicotine consumption and dopamine reward signals in the nucleus accumbens.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13437019.14811147 ◽

2012 ◽

Author(s):

Gregg Homanics ◽

David Werner

Keyword(s):

Protein Kinase C ◽

Nucleus Accumbens ◽

Protein Kinase ◽

Kinase C ◽

Protein Kinase C Epsilon ◽

Nicotine Consumption

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Proteomic Studies of Primary Acute Myeloid Leukemia Cells Derived from Patients Before and during Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid and Valproic Acid

Cancers ◽

10.3390/cancers13092143 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2143

Author(s):

Maria Hernandez-Valladares ◽

Rebecca Wangen ◽

Elise Aasebø ◽

Håkon Reikvam ◽

Frode S. Berven ◽

...

Keyword(s):

Valproic Acid ◽

Acute Myeloid Leukemia ◽

Retinoic Acid ◽

Protein Kinase ◽

Myeloid Leukemia ◽

Rna Metabolism ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Acute Myeloid

All-trans retinoic acid (ATRA) and valproic acid (VP) have been tried in the treatment of non-promyelocytic variants of acute myeloid leukemia (AML). Non-randomized studies suggest that the two drugs can stabilize AML and improve normal peripheral blood cell counts. In this context, we used a proteomic/phosphoproteomic strategy to investigate the in vivo effects of ATRA/VP on human AML cells. Before starting the combined treatment, AML responders showed increased levels of several proteins, especially those involved in neutrophil degranulation/differentiation, M phase regulation and the interconversion of nucleotide di- and triphosphates (i.e., DNA synthesis and binding). Several among the differentially regulated phosphorylation sites reflected differences in the regulation of RNA metabolism and apoptotic events at the same time point. These effects were mainly caused by increased cyclin dependent kinase 1 and 2 (CDK1/2), LIM domain kinase 1 and 2 (LIMK1/2), mitogen-activated protein kinase 7 (MAPK7) and protein kinase C delta (PRKCD) activity in responder cells. An extensive effect of in vivo treatment with ATRA/VP was the altered level and phosphorylation of proteins involved in the regulation of transcription/translation/RNA metabolism, especially in non-responders, but the regulation of cell metabolism, immune system and cytoskeletal functions were also affected. Our analysis of serial samples during the first week of treatment suggest that proteomic and phosphoproteomic profiling can be used for the early identification of responders to ATRA/VP-based treatment.

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Protein kinase C isoforms in normal and leukemic neutrophils: altered levels in leukemic neutrophils and changes during myeloid maturation in chronic myeloid leukemia

Leukemia Research ◽

10.1016/s0145-2126(01)00098-4 ◽

2002 ◽

Vol 26 (1) ◽

pp. 67-81 ◽

Cited By ~ 25

Author(s):

Nagaraj Balasubramanian ◽

Suresh H. Advani ◽

Surekha M. Zingde

Keyword(s):

Protein Kinase C ◽

Chronic Myeloid Leukemia ◽

Protein Kinase ◽

Myeloid Leukemia ◽

Kinase C ◽

Protein Kinase C Isoforms

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Protein kinase C mediates mutant N-Ras–induced developmental abnormalities in normal human erythroid cells

Blood ◽

10.1182/blood-2002-05-1358 ◽

2002 ◽

Vol 100 (12) ◽

pp. 4185-4192 ◽

Cited By ~ 20

Author(s):

Richard L. Darley ◽

Lorna Pearn ◽

Nader Omidvar ◽

Marion Sweeney ◽

Janet Fisher ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Myeloid Leukemia ◽

Colony Growth ◽

Developmental Abnormalities ◽

Ras Mutations ◽

Molecular Abnormalities ◽

Kinase C ◽

Poor Understanding ◽

Normal Human

RAS mutations are one of the most frequent molecular abnormalities associated with myeloid leukemia and preleukemia, yet there is a poor understanding of how they contribute to the pathogenesis of these conditions. Here, we describe the consequences of ectopic mutant N-Ras (N-Ras*) expression on normal human erythropoiesis. We show that during early (erythropoietin [EPO]–independent) erythropoiesis, N-Ras* promoted the amplification of a phenotypically primitive but functionally defective subpopulation of CD34+ erythroblasts. N-Ras* also up-regulated the expression of megakaryocyte antigens on human erythroblasts. Although early erythroblasts expressing N-Ras* were able to respond to erythropoietin and generate mature progeny, this occurred with greatly reduced efficiency, probably explaining the poor colony growth characteristics of these cells. We further report that this oncogene promoted the expression and activation of protein kinase C (PKC) and that the effects of N-Ras* on erythropoiesis could be abrogated or attenuated by inhibition of PKC. Similarly, the effects of this oncogene could be partially mimicked by treatment with PKC agonist. Together, these data suggest that expression of N-Ras* is able to subvert the normal developmental cues that regulate erythropoiesis by activating PKC. This gives rise to phenotypic and functional abnormalities commonly observed in preleukemia, suggesting a direct link between RAS mutations and the pathogenesis of preleukemia.

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