Phorbol Ester-induced G1 Phase Arrest Selectively Mediated by Protein Kinase Cδ-dependent Induction of p21

Nakagawa, Motonori; Oliva, José Luís; Kothapalli, Devashish; Fournier, Alaina K.; Assoian, Richard K.; Kazanietz, Marcelo G.

doi:10.1074/jbc.m505748200

Cited by 84 publications

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“…PKC␦-induced G 1 arrest is mediated through the transcriptional up-regulation of the cell cycle inhibitor p21 Cip1 (24). However, as shown in the present article, the paradox seems to be more complex, because in asynchronously growing NSCLC cells phorbol esters lead to the accumulation of cells in G 2 /M, thus suggesting multiple points of regulation in the cell cycle by PKCs.…”

mentioning

confidence: 38%

“…While PKC⑀ is mostly a mitogenic/ survival kinase, growth inhibitory roles have been ascribed to PKC␣ and/or PKC␦ in several cell models. We have previously described that PKC␦ mediates PMA-induced G 1 arrest in H358 cells (24). Expression levels of PKC␣, PKC␦, and PKC⑀ in H358 cells remained constant across the S phase (supplemental Fig.…”

Section: Pma-induced P21 Cip1 Up-regulation G 2 /M Arrest and Senesmentioning

confidence: 99%

“…Briefly, 24, 48, or 72 h after PMA treatment cells were pulse-labeled with 3 Ci/ml of [methyl-3 H]thymidine (Amersham Biosciences) for 3 h, followed by trichloroacetic acid precipitation and scintillation counting. For determination of cell cycle profile, cells were stained with propidium iodide (0.1 mg/ml) and analyzed by flow cytometry, as previously described (24).…”

Section: Methodsmentioning

confidence: 99%

“…activation with phorbol esters causes a profound inhibition of cell proliferation in lung cancer cells, and our previous work has identified a PKC␦-dependent inhibitory mechanism that limits cell progression from G 1 into S phase (24). However, when asynchronously growing H358 NSCLC cells were treated for 30 min with the PKC activator PMA (100 nM), a significant accumulation of cells in G 2 /M was observed, as determined by flow cytometry analysis ( To begin dissecting the mechanisms that lead to the accumulation of H358 cells in G 2 /M, we decided to synchronize cells with hydroxyurea (HU) and analyze the effects of PMA on S 3 G 2 progression.…”

Section: Pma Causes Irreversible G 2 /M Arrest In Nsclc Cells-pkcmentioning

confidence: 99%

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S-Phase-specific Activation of PKCα Induces Senescence in Non-small Cell Lung Cancer Cells

Oliva

Caino

Senderowicz

et al. 2008

Journal of Biological Chemistry

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Protein kinase C (PKC) has been widely implicated in positive and negative control of cell proliferation. We have recently shown that treatment of non-small cell lung cancer (NSCLC) cells with phorbol 12-myristate 13-acetate (PMA) during G 1 phase inhibits the progression into S phase, an effect mediated by PKC␦-induced up-regulation of the cell cycle inhibitor p21 Cip1 . However, PMA treatment in asynchronously growing NSCLC cells leads to accumulation of cells in G 2 /M. Studies in post-G 1 phases revealed that PMA induced an irreversible G 2 /M cell cycle arrest in NSCLC cells and conferred morphological and biochemical features of senescence, including elevated SA-␤-Gal activity and reduced telomerase activity. Remarkably, this effect was phase-specific, as it occurred only when PKC was activated in S, but not in G 1 , phase. Mechanistic analysis revealed a crucial role for the classical PKC␣ isozyme as mediator of the G 2 /M arrest and senescence, as well as for inducing p21 Cip1 an obligatory event for conferring the senescence phenotype. In addition to the unappreciated role of PKC isozymes, and specifically PKC␣, in senescence, our data introduce the paradigm that discrete PKCs trigger distinctive responses when activated in different phases of the cell cycle via a common mechanism that involves p21 Cip1 up-regulation.Activation of protein kinase C (PKC) 4 with phorbol esters and related natural compounds causes an array of effects on differentiation, mitogenesis, survival, apoptosis, and transformation. The diverse effects of phorbol esters both in normal and cancerous cells is due to the existence of numerous intracellular effectors, of which PKC isozymes have been the most widely characterized. The PKC family comprises 3 subfamilies that include 10 structurally related phospholipid-dependent serine/threonine kinases (1, 2). Members of the classical cPKC (␣, ␤I, ␤II, and ␥) and the novel nPKC (␦, ⑀, , and ) subfamilies are activated by phorbol esters and their cellular analogue, the second messenger diacylglycerol, which leads to redistribution (translocation) of the enzymes from cytosol to intracellular membrane compartments, where they phosphorylate specific substrates. The marked heterogeneity in the signaling events and cell type-specific responses triggered by phorbol esters could be explained by the distinctive pattern of expression and intracellular localization of PKC isozymes and their substrates, which ultimately results in selective pathway activation.One of the paradigms that best exemplifies the functional versatility of PKC isozymes is the regulation of the cell cycle machinery. It became evident in the last years that PKCs can impact on the cell cycle both in positive and negative manners with a strict degree of cell type and isozyme specificity. PKC isozymes have been shown to regulate the progression of cells from G 1 to S phase as well as with the transition from G 2 to M phase (3) via transcriptional, translational, and post-translational mechanisms. PKCs control the activity of cyc...

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mentioning

confidence: 38%

Section: Pma-induced P21 Cip1 Up-regulation G 2 /M Arrest and Senesmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Pma Causes Irreversible G 2 /M Arrest In Nsclc Cells-pkcmentioning

confidence: 99%

See 2 more Smart Citations

S-Phase-specific Activation of PKCα Induces Senescence in Non-small Cell Lung Cancer Cells

Oliva

Caino

Senderowicz

et al. 2008

Journal of Biological Chemistry

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“…Activation of PKCd inhibits the progression through G1 and G2 phases of the cell cycle. In lung cancer cells, for example, PKCd controls the expression of the cell cycle inhibitor p21 (20). In other models such as prostate cancer cells, PKCd activation leads to cell death response via the activation of the extrinsic apoptotic cascade (1).…”

Section: Future Directionsmentioning

confidence: 99%

PKC and Cancer: Time for a Comeback?

Kazanietz¹

2012

AACR Education book

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Peptide mimetic NC114 induces growth arrest by preventing PKCδ activation and FOXM1 nuclear translocation in colorectal cancer cells

Taguchi,

Nakaya,

Aizawa

et al. 2024

FEBS Open Bio

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The peptide mimetic, NC114, is a promising anticancer compound that specifically kills colorectal cancer cells without affecting normal colon epithelial cells. In our previous study, we observed that NC114 inhibited the Wnt/β‐catenin pathway, with significant downregulation of both Ser 675‐phosphorylated β‐catenin and its target genes, cyclin D1 and survivin. However, the molecular mechanism responsible for its cytotoxic effect has not yet been fully characterized. In the present study, we demonstrated that NC114 prevented cell cycle progression from S to G2/M phase by downregulating cell cycle‐related gene expression, and also induced growth arrest in SW480 and HCT‐116 colorectal cancer cells. A novel covariation network analysis combined with transcriptome analysis revealed a series of signaling cascades affected by NC114 treatment, and identified protein kinase C‐δ (PKCδ) and forkhead box protein M1 (FOXM1) as important regulatory factors for NC114‐induced growth arrest. NC114 treatment inhibits the activation of PKCδ and its kinase activity, which suppresses MEK/ERK signaling. Attenuated MEK/ERK signaling then results in a reduction in FOXM1 phosphorylation and subsequent nuclear translocation of FOXM1 and β‐catenin. Consequently, formation of a T‐cell factor‐4 (TCF4)/β‐catenin transcription complex in the nucleus is inhibited and transcription of its target genes, such as cell cycle‐related genes, is downregulated. The efficacy of NC114 on tumor growth was confirmed in a xenograft model. Collectively, elucidation of the mechanism by which NC114 induces growth arrest in colorectal cancer cells should provide a novel therapeutic strategy for colorectal cancer treatment.

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Phorbol Ester-induced G1 Phase Arrest Selectively Mediated by Protein Kinase Cδ-dependent Induction of p21

Cited by 84 publications

References 42 publications

S-Phase-specific Activation of PKCα Induces Senescence in Non-small Cell Lung Cancer Cells

S-Phase-specific Activation of PKCα Induces Senescence in Non-small Cell Lung Cancer Cells

PKC and Cancer: Time for a Comeback?

Peptide mimetic NC114 induces growth arrest by preventing PKCδ activation and FOXM1 nuclear translocation in colorectal cancer cells

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