Epigallocatechin‐3‐gallate induces cell death in acute myeloid leukaemia cells and supports all‐<i>trans</i> retinoic acid‐induced neutrophil differentiation via death‐associated protein kinase 2

Britschgi, Adrian; Simon, Hans‐Uwe; Tobler, Andreas; Fey, Martin F.; Tschan, Mario P.

doi:10.1111/j.1365-2141.2009.08040.x

Cited by 75 publications

(79 citation statements)

References 40 publications

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“…67LR has been identified as a cell surface EGCG receptor that mediates an antitumor effect of EGCG in vivo (12,13). Furthermore, 67LR is required for EGCG-induced selective killing of multiple myeloma and AML cells, whereas peripheral blood mononuclear cells (PBMC) are spared (2,3). Such findings provide a rationale for the clinical evaluation of EGCG as a 67LR-targeting drug.…”

Section: Introductionmentioning

confidence: 99%

“…The 67-kDa laminin receptor (67LR) is overexpressed in various cancers, including multiple myeloma (2), acute myeloid leukemia (AML; ref. 3), colorectal carcinoma (4), and breast carcinoma (5). Pathologic studies suggest that increased 67LR expression is correlated with lesions histologic severity and tumor progression (4).…”

Section: Introductionmentioning

confidence: 99%

“…The green tea polyphenol epigallocatechin-3-O-gallate (EGCG) inhibits tumor cell growth and induces apoptosis in cancer cells without adversely affecting normal cells (2,3,8). Several clinical trials have been conducted to evaluate its potential role in cancer treatment (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

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Sphingosine Kinase-1 Protects Multiple Myeloma from Apoptosis Driven by Cancer-Specific Inhibition of RTKs

Tsukamoto

Huang

Kumazoe

et al. 2015

Molecular Cancer Therapeutics

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Activation of acid sphingomyelinase (ASM) leads to ceramide accumulation and induces apoptotic cell death in cancer cells. In the present study, we demonstrate that the activation of ASM by targeting cancer-overexpressed 67-kDa laminin receptors (67LR) induces lipid raft disruption and inhibits receptor tyrosine kinase (RTK) activation in multiple myeloma cells. Sphingosine kinase 1 (SphK1), a negative regulator of ceramide accumulation with antiapoptotic effects, was markedly elevated in multiple myeloma cells. The silencing of SphK1 potentiated the apoptotic effects of the green tea polyphenol epigallocatechin-3-O-gallate (EGCG), an activator of ASM through 67LR. Furthermore, the SphK1 inhibitor safingol synergistically sensitized EGCG-induced proapoptotic cell death and tumor suppression in multiple myeloma cells by promoting the prevention of RTK phosphorylation and activation of death-associated protein kinase 1 (DAPK1). We propose that targeting 67LR/ASM and SphK1 may represent a novel therapeutic strategy against multiple myeloma.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sphingosine Kinase-1 Protects Multiple Myeloma from Apoptosis Driven by Cancer-Specific Inhibition of RTKs

Tsukamoto

Huang

Kumazoe

et al. 2015

Molecular Cancer Therapeutics

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“…In addition to its identified roles in erythropoiesis 8 and granulocyte maturation, 9 in recent studies, DAPK2 has been shown to be involved in the regulation of cell death in tumors induced by therapeutic agents. It is centrally involved in the epigallocatechin-3-gallateinduced cell death in acute myeloid leukemia, 38 and it is upregulated during the resveratrol-induced cell death of cancer stem-like cells isolated from breast cancer cell lines. 39 For a better understanding of these functions, a detailed structural analysis of the different states in the DAPK2 regulatory cascade must be carried out.…”

Section: Model For Dapk2 Autophosphorylation and Activationmentioning

confidence: 99%

Structure of the Dimeric Autoinhibited Conformation of DAPK2, a Pro-Apoptotic Protein Kinase

Patel

Yadav

Majava

et al. 2011

Journal of Molecular Biology

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The death-associated protein kinase (DAPK) family has been characterized as a group of pro-apoptotic serine/threonine kinases that share specific structural features in their catalytic kinase domain. Two of the DAPK family members, DAPK1 and DAPK2, are calmodulin-dependent protein kinases that are regulated by oligomerization, calmodulin binding, and autophosphorylation. In this study, we have determined the crystal and solution structures of murine DAPK2 in the presence of the autoinhibitory domain, with and without bound nucleotides in the active site. The crystal structure shows dimers of DAPK2 in a conformation that is not permissible for protein substrate binding. Two different conformations were seen in the active site upon the introduction of nucleotide ligands. The monomeric and dimeric forms of DAPK2 were further analyzed for solution structure, and the results indicate that the dimers of DAPK2 are indeed formed through the association of two apposed catalytic domains, as seen in the crystal structure. The structures can be further used to build a model for DAPK2 autophosphorylation and to compare with closely related kinases, of which especially DAPK1 is an actively studied drug target. Our structures also provide a model for both homodimerization and heterodimerization of the catalytic domain between members of the DAPK family. The fingerprint of the DAPK family, the basic loop, plays a central role in the dimerization of the kinase domain.

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“…Overexpression of DAPK2 results in morphological changes reminiscent of apoptosis in adherent cells, such as membrane blebbing and condensation of nuclei (5, 6), and in reduced viability and survival in suspension cells (12,13). In line with these findings, restoration of DAPK2 activity through fusion of a constitutively active DAPK2 to CD30 in Hodgkin lymphoma cells resulted in selective apoptosis in tumor cells in vitro and in prolonged survival in a Hodgkin lymphoma mouse model (14), and depletion of DAPK2 sensitizes resistant cells to TRAIL-induced killing (15).…”

mentioning

confidence: 99%

Identification of Novel Death-Associated Protein Kinase 2 Interaction Partners by Proteomic Screening Coupled with Bimolecular Fluorescence Complementation

Geering

Zokouri

Hürlemann

et al. 2016

Molecular and Cellular Biology

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e Death-associated protein kinase 2 (DAPK2) is a Ca 2؉ /calmodulin-dependent Ser/Thr kinase that possesses tumor-suppressive functions and regulates programmed cell death, autophagy, oxidative stress, hematopoiesis, and motility. As only few binding partners of DAPK2 have been determined, the molecular mechanisms governing these biological functions are largely unknown. We report the identification of 180 potential DAPK2 interaction partners by affinity purification-coupled mass spectrometry, 12 of which are known DAPK binding proteins. A small subset of established and potential binding proteins detected in this screen was further investigated by bimolecular fluorescence complementation (BiFC) assays, a method to visualize protein interactions in living cells. These experiments revealed that ␣-actinin-1 and 14-3-3-␤ are novel DAPK2 binding partners. The interaction of DAPK2 with ␣-actinin-1 was localized at the plasma membrane, resulting in massive membrane blebbing and reduced cellular motility, whereas the interaction of DAPK2 with 14-3-3-␤ was localized to the cytoplasm, with no impact on blebbing, motility, or viability. Our results therefore suggest that DAPK2 effector functions are influenced by the protein's subcellular localization and highlight the utility of combining mass spectrometry screening with bimolecular fluorescence complementation to identify and characterize novel protein-protein interactions. D eath-associated protein kinases (DAPKs) are a family of five Ser/Thr kinases that share a high degree of sequence homology in their catalytic domains but differ significantly in their extracatalytic domains. The best-studied member of the DAPK family is DAPK1, a regulator of programmed cell death (1, 2), autophagy (3), and motility (4).DAPK2 exhibits a kinase domain with 80% homology to the one of DAPK1 and also contains a calmodulin (CaM)-binding site (5, 6) but uniquely features a C-terminal homodimerization domain (6) while lacking the diverse protein-protein interaction domains that DAPK1 possesses (5, 6). The kinase is kept in an inactive conformation by a double-locking mechanism, which requires dephosphorylation of an autophosphorylated residue (Ser318) within the CaM-binding domain by a yet-to-be identified phosphatase in order to allow for CaM binding and homodimerization, both of which enhance kinase activity (7,8). Also the phosphorylation of Ser299 by cyclic GMP (cGMP)-dependent protein kinase I (9) and the interaction with 14-3-3-(10) regulate DAPK2 kinase activity. To date, the only known DAPK2 substrates are DAPK2 itself, regulatory light chain of myosin II (RLC), and mammalian target of rapamycin complex 1 (mTORC1) (5, 6, 11).DAPK2 was shown to mediate programmed cell death. Overexpression of DAPK2 results in morphological changes reminiscent of apoptosis in adherent cells, such as membrane blebbing and condensation of nuclei (5, 6), and in reduced viability and survival in suspension cells (12,13). In line with these findings, restoration of DAPK2 activity through fusion of a consti...

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Epigallocatechin‐3‐gallate induces cell death in acute myeloid leukaemia cells and supports all‐trans retinoic acid‐induced neutrophil differentiation via death‐associated protein kinase 2

Cited by 75 publications

References 40 publications

Sphingosine Kinase-1 Protects Multiple Myeloma from Apoptosis Driven by Cancer-Specific Inhibition of RTKs

Sphingosine Kinase-1 Protects Multiple Myeloma from Apoptosis Driven by Cancer-Specific Inhibition of RTKs

Structure of the Dimeric Autoinhibited Conformation of DAPK2, a Pro-Apoptotic Protein Kinase

Identification of Novel Death-Associated Protein Kinase 2 Interaction Partners by Proteomic Screening Coupled with Bimolecular Fluorescence Complementation

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