The Polyether Bistratene A Activates Protein Kinase C–δ and Induces Growth Arrest in HL60 Cells

Griffiths, Gareth; Garrone, Bernadette; Deacon, E. M.; Owen, P J; Pongrácz, Judit E.; Mead, Graham P.; Bradwell, Arthur; Watters, Dianne Josephine; Lord, Janet

doi:10.1006/bbrc.1996.0830

Cited by 80 publications

(69 citation statements)

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“…Early work from Mischak et al (36) showed that overexpression of PKC␦ in NIH 3T3 fibroblasts inhibits cell growth, in contrast to the effect observed with PKC⑀, which promotes cell growth and transformation in this cell type. In other cell types, such as CHO or HL-60 cells, ectopic expression of PKC␦ leads G 2 /M arrest (37,38). On the other hand, PKC␦ enhances anchorage-independent growth and metastatic potential in mammary adenocarcinoma cells (39).…”

Section: Discussionmentioning

confidence: 99%

Diacylglycerol (DAG)-lactones, a New Class of Protein Kinase C (PKC) Agonists, Induce Apoptosis in LNCaP Prostate Cancer Cells by Selective Activation of PKCα

García‐Bermejo¹,

Leskow²,

Fujii³

et al. 2002

Journal of Biological Chemistry

113

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Phorbol esters, the archetypical (PKC) activators, induce apoptosis in androgen-sensitive LNCaP prostate cancer cells. In this study we evaluate the effect of a novel class of PKC ligands, the diacylglycerol (DAG)-lactones, as inducers of apoptosis in LNCaP cells. These unique ligands were designed using novel pharmacophore-and receptorguided approaches to achieve highly potent DAG surrogates. Two of these compounds, HK434 and HK654, induced apoptosis in LNCaP cells with much higher potency than oleoyl-acetyl-glycerol or phorbol 12,13-dibutyrate. Moreover, different PKC isozymes were found to mediate the apoptotic effect of phorbol 12-myristate 13-acetate (PMA) and HK654 in LNCaP cells. Using PKC inhibitors and dominant negative PKC isoforms, we found that both PKC␣ and PKC␦ mediated the apoptotic effect of PMA, whereas only PKC␣ was involved in the effect of the DAG-lactone. The PKC␣ selectivity of HK654 in LNCaP cells contrasts with similar potencies in vitro for binding and activation of PKC␣ and PKC␦. Consistent with the differences in isoform dependence in intact cells, PMA and HK654 show marked differences in their abilities to translocate PKC isozymes. Both PMA and HK654 induce a marked redistribution of PKC␣ to the plasma membrane. On the other hand, unlike PMA, HK654 translocates PKC␦ predominantly to the nuclear membrane. Thus, DAG-lactones have a unique profile of activation of PKC isozymes for inducing apoptosis in LNCaP cells and represent the first example of a selective activator of a classical PKC in cellular models. An attractive hypothesis is that selective activation of PKC isozymes by pharmacological agents in cells can be achieved by differential intracellular targeting of each PKC.The phorbol esters and related diterpenes are natural compounds that have been for many years the preferred pharmacological tools for studying protein kinase C (PKC), 1 a key family of kinases implicated in growth factor-and G-proteincoupled receptor signaling. These compounds mimic the action of the lipid second messenger diacylglycerol (DAG), a relatively simple and highly flexible molecule generated by cellular phospholipases. The higher potency of phorbol esters and their greater stability compared with the second messenger DAG makes these agents the preferred activators of PKC (1, 2). Phorbol esters regulate a variety of cellular functions, including cell cycle progression, differentiation, cytoskeleton remodeling, and malignant transformation. Although phorbol esters promote mitogenesis in several cell types, accumulating data indicate that activation of PKC leads to inhibition of cell growth in many cells (3-6). Interestingly, phorbol esters induce apoptosis in several cell lines, including thymocytes, breast cancer cells, and prostate cancer cells (7-12).The heterogeneity of effects of the phorbol esters is related to the presence of multiple phorbol ester/DAG receptors, including PKC isozymes and "nonkinase" PKC receptors. The PKC family comprises at least 10 related kinases with differential expression, ...

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Section: Discussionmentioning

confidence: 99%

Diacylglycerol (DAG)-lactones, a New Class of Protein Kinase C (PKC) Agonists, Induce Apoptosis in LNCaP Prostate Cancer Cells by Selective Activation of PKCα

García‐Bermejo¹,

Leskow²,

Fujii³

et al. 2002

Journal of Biological Chemistry

113

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“…Following treatment with bile acid and butyrate, cells were harvested by scraping, lysed and cytosol (soluble) and membrane (particulate) fractions were isolated by centrifugation as previously described (Griffiths et al, 1996). Briefly cell lysates were spun at 100 000 Â g for 45 min at 41C, the supernatant (soluble fraction) was removed and the pellet (particulate fraction) was extracted in lysis buffer (50 mM Tris-HCl, pH 7.4, 5 mM MgCl 2 , 1 mM EGTA, 1 mM EDTA, 100 mg ml À1 leupeptin, 10 mg ml À1 pepstatin and 1 mM PMSF) containing 0.5% Triton X-100.…”

Section: Assessment Of Pkc Isoenzyme Activationmentioning

confidence: 99%

Opposing effects of butyrate and bile acids on apoptosis of human colon adenoma cells: differential activation of PKC and MAP kinases

et al. 2003

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Butyrate, produced in the colon by fermentation of dietary fibre, induces apoptosis in colon adenoma and cancer cell lines, which may contribute to protection against colorectal cancer. However, butyrate is present in the colon along with other dietary factors, including unconjugated bile acids, which are tumour promoters. We have shown previously that the proapoptotic effects of butyrate on AA/C1 human adenoma cells were reduced in the presence of bile acids. To determine the cellular basis of this interaction, we examined the effects of butyrate and the secondary bile acid ursodeoxycholic acid (UDCA) on signalling pathways known to regulate apoptosis using AA/C1 cells. Butyrate activated PKC-d and p38 MAP (mitogen-activated protein) kinase, whereas UDCA activated PKC-a and p42/44 MAP kinase. Butyrate treatment also resulted in the caspase-3-mediated proteolysis of PKC-d. Butyrate-induced apoptosis was reduced by inhibitors of PKC-d (Rottlerin), p38 MAP kinase (SB202190) and caspase 3 (DEVD-fmk), whereas the proliferative/survival effects of UDCA were blocked by inhibitors of PKC-a (Gö 6976) and MEK 1 (PD98059). The effects of butyrate and bile acids are therefore mediated by the differential activation of signalling pathways that are known to regulate apoptosis.

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“…This inhibition was accompanied by the appearance of dikaryotic and sometimes tetrakaryotic cells, presumably due to a failure in cytokinesis [70]. BisA, a selective activator of PKCG, also induced G2/M arrest and cell adhesion of HL60 cells [71]. How the activation of PKCS by BisA could affect growth arrest in G2/M is not known.…”

Section: Pkc Acts During G1 Progression and The G 2 M Transition In Mmentioning

confidence: 99%

“…How the activation of PKCS by BisA could affect growth arrest in G2/M is not known. Interestingly, BisA also induced translocation of PKCG to the nucleus, inhibition of cytokinesis, and the formation of multinuclear cells [71]. [72].…”

Section: Pkc Acts During G1 Progression and The G 2 M Transition In Mmentioning

confidence: 99%

Linking Protein Kinase C to Cell‐Cycle Control

Livneh

Fishman

1997

European Journal of Biochemistry

199

114

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Protein kinase C (PKC) isoenzymes are involved in diverse cellular functions, including differentiation, growth control, tumor promotion, and cell death. In recent years, evidence has began to emerge suggesting a role for PKC in cell cycle control. A paper published recently, demonstrating a functional link between PKC and cell cycle control in yeast (Marini, N. J., Meldrum, E., Buehrer, B., Hubberstey, A. V., Stone, D. E., Traynor-Kaplan, A. & Reed, S. I. (1996) EMBO J. 15, 3040-3052), strengthens this data. Thus, the existence of cell-cycle-regulated pathways involving PKC in both yeast and mammals indicate that PKC may be a conserved regulator of cell cycle events that links signal transduction pathways and the cell-cycle machinery. In this paper, we will review current data on the cell cycle components that are targets for PKC regulation.PKC enzymes appear to operate as regulators of the cell cycle at two sites, during G1 progression and G 2 M transition. In G1, the overall effect of PKC activation is inhibition of the cell cycle at mid to late G1. This cell cycle inhibition correlates with a blockage in the normal phosphorylation of the tumor suppressor retinoblastoma Rb protein, presumably through an indirect mechanism. The reduced activity of the cyclin-dependent kinase, Cdk2, appears to be the major effect of PKC activation in various cell systems. This may also underlie the inhibition of Rb phosphorylation exhibited by PKC activation. Several mechanisms were described in different studieq on the regulation of Cdk2 activity by PKC; reduced Cdk-activating kinase activity, diminished expression of the Cdk2 partners cyclins E or A, and the increased expression of the cyclin-dependent inhibitors, p2lWAF1 and p27K'P', which are capable of binding to cyclidCdk2 complexes.PKC enzymes were also shown to play a role in G2/M transition. Among the suggested mechanisms is suppression of Cdc2 activity. However, most of the published data strongly implicate PKC in lamin B phosphorylation and nuclear envelope disassembly.Keywords: protein kinase C ; cell cycle; cyclin ; cyclin-dependent kinase; Cdk inhibitor; retinoblastoma protein; p53 protein; phorbol ester; GUS transition; G2/M transition. Protein kinase C and growth regulationThe term protein kinase C (PKC) stands for a group of at least ten serinehhreonine kinases that are characterized by a high degree of similarity in their catalytic kinase domains and cysteine-rich regions [l-41. The PKC family is subdivided into three groups; the classical PKC members (a, p, y) are Ca2+ and diacylglycerol-dependent, the novel PKCs (6, E , q and d) are Ca2+-independent but diacylglycerol-dependent and the atypical PKCs ([ and 2) are not activated by Ca*+ and diacylglycerol in vitro [3, 41. This may account for the multiplicity and diversity of the cellular activities implicated to be mediated by PKC, sinceCorrespondence to

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The Polyether Bistratene A Activates Protein Kinase C–δ and Induces Growth Arrest in HL60 Cells

Cited by 80 publications

References 0 publications

Diacylglycerol (DAG)-lactones, a New Class of Protein Kinase C (PKC) Agonists, Induce Apoptosis in LNCaP Prostate Cancer Cells by Selective Activation of PKCα

Diacylglycerol (DAG)-lactones, a New Class of Protein Kinase C (PKC) Agonists, Induce Apoptosis in LNCaP Prostate Cancer Cells by Selective Activation of PKCα

Opposing effects of butyrate and bile acids on apoptosis of human colon adenoma cells: differential activation of PKC and MAP kinases

Linking Protein Kinase C to Cell‐Cycle Control

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