Abrogation of Mitochondrial Cytochrome c Release and Caspase-3 Activation in Acquired Multidrug Resistance

Kojima, Hiromi; Endo, Kazuya; Moriyama, Hiroshi; Tanaka, Yasuhiro; Alnemri, Emad S.; Slapak, Christopher A.; Teicher, Beverly A.; Küfe, Donald; Datta, Rakesh

doi:10.1074/jbc.273.27.16647

Cited by 118 publications

(96 citation statements)

References 25 publications

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“…In fact, abrogation of mitochondrial Cytochrome c release has been associated with cellular resistance to multiple drugs, including cDDP. 23 In addition, mitochondrial translocation of PKCd has been associated with apoptotic cell death in several cell types, including keratinocytes, 38 U-937 and MCF-7 cells. 39 Furthermore, PKC activator induced release of Cytochrome c and rottlerin attenuated Cytochrome c release by PKC activators.…”

Section: Discussionmentioning

confidence: 99%

“…22 An inability to induce release of Cytochrome c from mitochondria has been associated with cellular resistance to anticancer agents, including cDDP. 23 In the present study, we have investigated how PKC regulates release of Cytochrome c and activation of caspases that emanate from mitochondria. Our results show that in HeLa cells, PKCd was localized not only in the cytosol but also in the mitochondrial fraction and cDDP induced processing of both cytosolic and membrane-associated PKCd.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of protein kinase C-δ in DNA damage-induced apoptosis

2001

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We have previously shown that the protein kinase C (PKC) signal transduction pathway regulates cell death by the DNA damaging agent cis-diamminedichloroplatinum(II) (cDDP). In the present study we have investigated how PKC influences the sequence of events that are triggered by cDDP-induced DNA damage. cDDP caused activation of caspases-8, -9, -3, -7 and cleavage of PKCd. Rottlerin, a selective inhibitor of novel PKCd, blocked activation of caspases, proteolytic activation of PKCd and cell death induced by cDDP. In contrast, Go È 6976, an inhibitor of conventional PKCa and bI, did not prevent cDDP-induced caspase activation and cDDP cytotoxicity. In HeLa cells, PKCd was distributed both in the cytosol and heavy membrane (HM) fraction containing mitochondria. While caspase-8 was primarily cytosolic, a small amount of caspases-9, -7 and -3 could be detected in the HM fraction. cDDP caused a time-dependent increase in Cytochrome c release from the mitochondria and processing of both cytosolic and membrane-associated caspases, as well as proteolytic cleavage of PKCd. Rottlerin attenuated late but not early release of Cytochrome c by cDDP. It, however, inhibited activation of caspases and proteolytic cleavage of PKCd in both cytosolic and HM fractions. The antiapoptotic effect of rottlerin was evident when it was added together with or following cDDP addition but not when added after cDDP was removed from the medium. Thus, the PKCd inhibitor acts at an early stage of the cDDP-induced cell death pathway that precedes caspase activation. Cell Death and Differentiation (2001) 8, 899 ± 908.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Involvement of protein kinase C-δ in DNA damage-induced apoptosis

2001

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“…To assess the effects of MUC1 on chemosensitivity, we treated 3Y1 cells with araC, an antimetabolite that induces the release of mitochondrial cytochrome c and thereby apoptosis (40,41). Exposure of 3Y1/vector-A and -B cells to araC was associated with a decrease in mitochondrial transmembrane potential (⌬⌿m) (Fig.…”

Section: Muc1mentioning

confidence: 99%

The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

Raina

Kharbanda

Küfe

2004

Journal of Biological Chemistry

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154

144

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The MUC1 transmembrane glycoprotein is overexpressed by most human carcinomas. Overexpression of MUC1 confers transformation; however, the signaling pathways activated by this oncoprotein are largely unknown. The present studies demonstrated that MUC1-induced transformation of 3Y1 fibroblasts is associated with increased levels of phospho-Akt and phospho-Bad. The finding that LY294002 blocks MUC1-mediated increases in phospho-Akt and phospho-Bad supports the involvement of phosphoinositide 3-kinase (PI3K) as an upstream effector of this response. We also show that MUC1 increases the expression of the anti-apoptotic Bcl-x L protein (but not Bcl-2) by a PI3K-independent mechanism. In concert with these results, MUC1 attenuated (i) the loss of mitochondrial transmembrane potential, (ii) mitochondrial cytochrome c release, (iii) activation of caspase-9, and (iv) induction of apoptosis by the antimetabolite, 1-␤-D-arabinofuranosylcytosine. Similar results were obtained with the anti-cancer agent, gemcitabine. These findings indicate that expression of MUC1 in 3Y1 cells activates the anti-apoptotic PI3K/Akt and Bcl-x L pathways.The phosphoinositide 3-kinase (PI3K) 1 /Akt signaling pathway is of importance in promoting cell survival. PI3K, which consists of a p85 regulatory subunit and a p110 catalytic subunit, phosphorylates phosphatidylinositols (PIs) at their 3-position and thereby converts PI(4,5)P 2 to PI(3,4,5)P 3 (1). The serine-threonine Akt/PKB kinase and the phosphoinositide-dependent kinase 1 (PDK1) localize at cell membrane sites by direct binding to PI(3,4,5)P 3 through their pleckstrin-homology domains (2, 3). Phosphorylation of Akt by PDK1 stimulates Akt activity (4). In turn, Akt phosphorylates and inactivates the Forkhead-related transcription factor 1 by retaining it in the cytosol in a complex with 14-3-3 proteins. Similarly, Akt phosphorylates Bad, induces binding of Bad to 14-3-3 proteins, and prevents Bad from interacting with the anti-apoptotic Bcl-2 and Bcl-x L proteins (5). The activity of the pro-death caspase-9 protease is inhibited by Akt-mediated phosphorylation (6). Akt can also confer cell survival by indirect regulation of NF-B through I B kinase (7, 8) and of p53 through Mdm2 (9, 10). These findings, and the demonstration that PI3K/Akt signaling is dysregulated in human malignancies, have provided support for the significance of this pathway in conferring tumor cell survival (11).The human DF3/MUC1 transmembrane glycoprotein is expressed on the apical borders of normal secretory epithelial cells (12). The MUC1 protein is synthesized as a single polypeptide that is cleaved in the endoplasmic reticulum into N-terminal and C-terminal subunits, which then reside as heterodimers at the apical cell surface (13,14). The large (Ͼ250 kDa) N-terminal ectodomain (N-ter) contains variable numbers of 20-amino acid tandem repeats that are heavily glycosylated (15, 16). The smaller (ϳ25 kDa) C-terminal subunit (C-ter) consists of an extracellular domain of 58 amino acids, a 28-amino acid transmembrane...

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“…One of the main model proteins used is ubiquitin (Ub), commercially available in high purity, with a reasonably low molecular weight (8.6 kDa It is worth noting that, although cisplatin has been described as playing a potential role in the release of Cyt c from mitochondria to the cytoplasm, [107][108][109] this protein has been mainly used as model system in MS experiments. [104,110,111] Interestingly, while previous studies using different investigational methods, including MS, showed that cisplatin, transplatin, oxaliplatin and carboplatin possess different stabilities and reactivity with protein/peptides in physiological media, MS revealed that the compounds' behaviour towards Cyt c is quite similar.…”

Section: Ubiquitin (Ub)mentioning

confidence: 99%

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

Wenzel

Casini

2017

Coordination Chemistry Reviews

108

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Metal-based compounds form a promising class of therapeutic agents, whose mechanisms of action still need to be elucidated, and that are in general prone to undergo extensive speciation in physiological environment. Thus, determination of the fate of the metal compounds in complex biological systems, contributing to their overall pharmacological and toxicological profiles, is important to develop more rationalised and targeted metal-based drugs. To these aims, a number of spectroscopic and biophysical methods, as well as analytical techniques, are nowadays extensively applied to study the reactivity of metal complexes with different biomolecules (e.g. nucleic acids, proteins, buffer components). Among the various techniques, molecular mass spectrometry (MS) has emerged in the last decade as a major tool to characterise the interactions of metallodrugs at a molecular level. In this review, we present an overview of the information available on the reactivity of various families of therapeutic metallodrugs (mainly anticancer compounds based on Pt, Ru, Au and As) with biomolecules studied by different MS techniques, including high-resolution ESI-, MALDI-and ion mobility-MS among others. Representative examples on the potential of the MS approach to study non-covalent interactions are also discussed. The review is organized to present results obtained on samples with different degrees of complexity, from the interactions of metal compounds with small model nucleophiles (amino acids and nucleobases), model peptides/oligonucleotides, target proteins/nucleic acids, to the analysis of serum, cell extracts and tissue samples. The latter requiring combination of proteomic methods with advanced MS techniques. Correlations between molecular reactivity of metallodrugs and biological activity are hard to establish, but differences in the reactivity of metallodrugs to biomolecules and their different adducts, as revealed by MS methods, may indicate differences in their modes of action. Overall, the knowledge offered by MS methods on metallodrugs speciation is invaluable to establish new rules and define new trends in the periodic table aimed at rationalizing the behavior of metal compounds in complex living systems. Keywordsmetal-based drugs; proteins; nucleic acids; mass spectrometry; metallomics. Corresponding Author Angela Casini Corresponding Author's InstitutionCardiff University To view all the submission files, including those not included in the PDF, click on the manuscript title on your EVISE Homepage, then click 'Download zip file'. Order of Authors 1 Answers to Reviewers Reviewer 1 The authors have made some effort to answer suggestions and the manuscript is improved. Since it is a review, there is, strictly, no new information but nevertheless the compilation of data and references could be useful.Answer: no further comments. Liu et al." in place of "Lu et al." iv) Some symbols in the PDF file are not correctly displayed. Reviewer Answer:We have inserted all the minor modifications requested by this rev...

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Abrogation of Mitochondrial Cytochrome c Release and Caspase-3 Activation in Acquired Multidrug Resistance

Cited by 118 publications

References 25 publications

Involvement of protein kinase C-δ in DNA damage-induced apoptosis

Involvement of protein kinase C-δ in DNA damage-induced apoptosis

The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

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