Protein kinase C (PKC) isoforms in cancer, tumor promotion and tumor suppression

Isakov, Noah

doi:10.1016/j.semcancer.2017.04.012

Cited by 197 publications

(146 citation statements)

References 255 publications

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“…Further evidence that phorbol ester-dependent loss of PKC could be driving tumorigenesis came from studies by Altman and coworkers that showed that long-term treatment of a metastatic fibrosarcoma cell line with PDBu, resulting in a 4-fold reduction in PKC activity, increased lung tumor formation following intravenous injection of the cells in mice (Isakov et al 1991; Isakov 2017). In contrast, a single short-term exposure to PDBu, shown to acutely activate PKC, decreased the cell’s ability to form lung metastasis.…”

Section: Phorbol Esters Tumor Promotion and Down-regulationmentioning

confidence: 99%

Protein kinase C: perfectly balanced

Newton

2018

Critical Reviews in Biochemistry and Molecular Biology

213

193

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Protein kinase C (PKC) isozymes belong to a family of Ser/Thr kinases whose activity is governed by reversible release of an autoinhibitory pseudosubstrate. For conventional and novel isozymes, this is effected by binding the lipid second messenger, diacylglycerol, but for atypical PKC isozymes, this is effected by binding protein scaffolds. PKC shot into the limelight following the discovery in the 1980s that the diacylglycerol-sensitive isozymes are ‘receptors’ for the potent tumor-promoting phorbol esters. This set in place a concept that PKC isozymes are oncoproteins. Yet three decades of cancer clinical trials targeting PKC with inhibitors failed and, in some cases, worsened patient outcome. Emerging evidence from cancer-associated mutations and protein expression levels provide a reason: protein kinase C isozymes generally function as tumor suppressors and their activity should be restored, not inhibited, in cancer therapies. And whereas not enough activity is associated with cancer, variants with enhanced activity are associated with degenerative diseases such as Alzheimer’s disease. This review describes the tightly controlled mechanisms that ensure PKC activity is perfectly balanced and what happens when these controls are deregulated. PKC isozymes serve as a paradigm for the wisdom of Confucius: “to go beyond is as wrong as to fall short.”

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Section: Phorbol Esters Tumor Promotion and Down-regulationmentioning

confidence: 99%

Protein kinase C: perfectly balanced

Newton

2018

Critical Reviews in Biochemistry and Molecular Biology

213

193

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“…The protein kinase C (PKC) family consists of many distinct proteins with different functions and tissue distributions. 20,21 In cardiac tissue, PKC α and PKC β2 are the predominant PKC isoforms. 22 Altered PKC expression and function has been linked to many cardiovascular disease-associated issues including heart failure and ischemia, and PKC inhibition has been shown to protect against structural and functional issues.…”

Section: Introductionmentioning

confidence: 99%

FBXL10 regulates cardiac dysfunction in diabetic cardiomyopathy via the PKC β2 pathway

Yin

Fang

Song

et al. 2019

J Cellular Molecular Medi

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Diabetic cardiomyopathy (DCM) is a condition associated with significant structural changes including cardiac tissue necrosis, localized fibrosis, and cardiomyocyte hypertrophy. This study sought to assess whether and how FBXL10 can attenuate DCM using a rat streptozotocin (STZ)‐induced DCM model system. In the current study, we found that FBXL10 expression was significantly decreased in diabetic rat hearts. FBXL10 protected cells from high glucose (HG)‐induced inflammation, oxidative stress, and apoptosis in vitro. In addition, FBXL10 significantly activated PKC β2 signaling pathway in H9c2 cells and rat model. The cardiomyocyte‐specific overexpression of FBXL10 at 12 weeks after the initial STZ administration attenuated oxidative stress and inflammation, thereby reducing cardiomyocyte death and preserving cardiac function in these animals. Moreover, FBXL10 protected against DCM via activation of the PKC β2 pathway. In conclusion, FBXL has the therapeutic potential for the treatment of DCM.

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“…PKC enzymes are regulated at the level of structure, function and subcellular localization [1][2][3][4][5][6][7][8][9]. PKC enzyme dysfunction has been linked to many human disease pathologies, including cancer, diabetes and heart disease [10][11][12][13][14][15][16][17]. PKC modulates aspects of cellular physiology, such as angiogenesis, cellular motility, proliferation, differentiation and apoptosis [18].…”

Section: Introductionmentioning

confidence: 99%

“…PKC modulates aspects of cellular physiology, such as angiogenesis, cellular motility, proliferation, differentiation and apoptosis [18]. Differential expression and activity of PKC has been linked to most types of cancer, including carcinomas (e.g., breast, colorectal), sarcomas (e.g., glioma), lymphomas (e.g., diffuse large Bcell lymphoma) and leukemias [10][11][12][13][14][15]. Generally, loss of PKC function has been linked to cancer, whereas enhanced activity has been linked to neurodegeneration [16].…”

Section: Introductionmentioning

confidence: 99%

“…Generally, loss of PKC function has been linked to cancer, whereas enhanced activity has been linked to neurodegeneration [16]. Many groundbreaking investigations during the last two decades have suggested that PKC enzymes have novel therapeutic potential as drug targets in different cancers, heart failure and neurodegenerative diseases [10][11][12][13][14][15][16][17][18][19]. Diverse catalytic and regulatory mechanisms exist within the PKC enzyme family, providing a plethora of possibilities for drug target design [18][19][20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

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A systems biology-based molecular model of the protein kinase C life cycle

Aslam

Alvi

2019

Preprint

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Protein kinase C (PKC) enzymes are a family of kinases that mediate signal transduction originating at the cell surface. Most cell membranes can contain functional PKC enzymes. Aberrations in the PKC life cycle may result cellular damage and dysfunction. For example, some cancerous cells exhibit alterations in PKC activity. Here, we use a systems biology approach to describe a molecular model of the PKC life cycle. Understanding the PKC life cycle is necessary to identify new anticancer drug targets. The PKC life cycle is composed of three key regulatory processes: maturation, activation and termination. These processes precisely control PKC enzyme levels. This model describes the fate of PKC during de novo synthesis and PKC's lipid-mediated activation cycle. We utilize a systems biology approach to show the PKC life cycle is controlled by multiple phosphorylation and dephosphorylation events. PKC processing events can be divided into two types: maturation via processing of newly synthesized enzyme and secondary messenger-dependent activation of dormant, but catalyticallycompetent enzyme. Newly synthesized PKC enzyme is constitutively processed through three ordered phosphorylations and stored in the cytosol as a stable, signaling-competent inactive and autoinhibited molecule. Upon extracellular stimulation, diacylglycerol (DAG) and calcium ion (Ca +2 ) generated at the membrane bind PKC. PKC then undergoes cytosol-to-membrane translocation and subsequent activation. Our model shows that, once activated, PKC is prone to dephosphorylation and subsequent degradation. This model also describes the role of HSP70 in stabilization and re-phosphorylation of dephosphorylated PKC, replenishing the PKC pool. Our model shows how the PKC pool responds to different intensities of extracellular stimuli? We show that blocking PHLPP dephosphorylation replenishes the PKC pool in a dose-dependent manner. This model provides a comprehensive understanding of PKC life cycle regulation.

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Protein kinase C (PKC) isoforms in cancer, tumor promotion and tumor suppression

Cited by 197 publications

References 255 publications

Protein kinase C: perfectly balanced

Protein kinase C: perfectly balanced

FBXL10 regulates cardiac dysfunction in diabetic cardiomyopathy via the PKC β2 pathway

A systems biology-based molecular model of the protein kinase C life cycle

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