Protein kinase Cα promotes apoptotic cell death in gastric cancer cells depending upon loss of anchorage

Okuda, Hiroyuki; Adachi, Masaaki; Miyazawa, Masaaki; Hinoda, Yuji; Imai, Kohzoh

doi:10.1038/sj.onc.1202946

Cited by 28 publications

(16 citation statements)

References 34 publications

(19 reference statements)

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“…Anti-apoptotic effects have also been ascribed to other PKC isozymes, including PKC⑀ and the atypical PKCs (49,50). Despite the growthpromoting effect described for PKC␣, this cPKC inhibits proliferation or has pro-apoptotic properties in many cellular models (3,6,51). Given the growth inhibitory properties of PKC isozymes, an emerging theme is that PKC activation rather than PKC inhibition may have therapeutic value in appropriate systems, and indeed several PKC agonists are under evaluation as anti-cancer agents in clinical studies (52)(53)(54).…”

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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“…PKC family members can have both proapoptotic and antiapoptotic effects on eukaryotic cells that depend on the PKC isoform and the cell type studied. For example, PKC-␣, -␤, and -␦ have been shown to induce cell death (22,32,37), whereas PKC- Fig. 5.…”

Section: Discussionmentioning

confidence: 99%

Chondrocyte cell death mediated by reactive oxygen species-dependent activation of PKC-βI

DelCarlo¹,

Loeser²

2006

American Journal of Physiology-Cell Physiology

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DelCarlo, Marcello, and Richard F. Loeser. Chondrocyte cell death mediated by reactive oxygen species-dependent activation of PKC-␤I. Am J Physiol Cell Physiol 290: C802-C811, 2006. First published October 19, 2005 doi:10.1152/ajpcell.00214.2005.-Signals generated by the extracellular matrix (ECM) promote cell survival. We have shown that chondrocytes detached from their native ECM and plated without serum at low density on poly-L-lysine undergo significant cell death that is associated with the production of reactive oxygen species (ROS). No cell death or ROS production was observed when cells were plated on fibronectin under the same conditions. Cell death on poly-L-lysine could be completely inhibited with the addition of either antioxidants or inhibitors of specific protein kinase C (PKC) isoforms including PKC-␤I. PKC-␤I was noted to translocate from the cytosol to the particulate membrane after plating on poly-L-lysine, and this translocation was inhibited by the addition of an antioxidant. Time-course analyses implicated endogenous ROS production as a secondary messenger leading to PKC-␤I activation and subsequent chondrocyte cell death. Cell survival on poly-L-lysine was significantly improved in the presence of oligomycin or DIDS, suggesting that ROS production occurred via complex V of the electron transport chain of the mitochondria and that ROS were released to the cytosol via voltage-dependent anion channels. Together, these results represent a novel mechanism by which ROS can initiate cell death through the activation of PKC-␤I. articular cartilage; osteoarthritis; cell signaling; fibronectin CELL CONTACT with the extracellular matrix (ECM) promotes survival in many cell types, but the exact mechanism is not completely understood. Studies have shown apoptotic cell death in epithelial (9) and endothelial

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“…Thus, inhibition of PKC may enhance antiproliferative and proapoptotic signaling in gastric cancer cells thereby increasing the therapeutic efficacy for gastric cancer [158][159][160][161]. In contrast, addition of TPA to gastric cancer cells enhances PKC -mediated cell apoptosis [162,163].…”

Section: General Gastric Carcinomamentioning

confidence: 99%

Protein Kinase C (PKC) Isozymes and Cancer

Kang

2014

New Journal of Science

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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.

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Protein kinase Cα promotes apoptotic cell death in gastric cancer cells depending upon loss of anchorage

Cited by 28 publications

References 34 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

Chondrocyte cell death mediated by reactive oxygen species-dependent activation of PKC-βI

Protein Kinase C (PKC) Isozymes and Cancer

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