Long-term incubation with proteasome inhibitors (PIs) induces IκBα degradation via the lysosomal pathway in an IκB kinase (IKK)-dependent and IKK-independent manner.
Identifieur interne : 000214 ( Ncbi/Checkpoint ); précédent : 000213; suivant : 000215Long-term incubation with proteasome inhibitors (PIs) induces IκBα degradation via the lysosomal pathway in an IκB kinase (IKK)-dependent and IKK-independent manner.
Auteurs : Kyoung-Hee Lee ; Jiyeong Jeong ; Chul-Gyu YooSource :
- The Journal of biological chemistry [ 1083-351X ] ; 2013.
Descripteurs français
- KwdFr :
- Acides boroniques (pharmacologie), Antinéoplasiques (pharmacologie), Bortézomib, Cétones (pharmacologie), Dipeptides (pharmacologie), Facteur de transcription NF-kappa B (métabolisme), Facteurs temps, Glycogen Synthase Kinase 3 (génétique), Glycogen Synthase Kinase 3 (métabolisme), Glycogen synthase kinase 3 beta, Humains, I-kappa B Kinase (génétique), I-kappa B Kinase (métabolisme), Inhibiteur alpha de NF-KappaB, Inhibiteurs du protéasome (pharmacologie), Interleukine-8 (biosynthèse), Interleukine-8 (génétique), Leupeptines (pharmacologie), Lignée cellulaire tumorale, Lysosomes (génétique), Lysosomes (métabolisme), Mutation faux-sens, Protéines I-kappa B (génétique), Protéines I-kappa B (métabolisme), Protéines associées aux microtubules (génétique), Protéines associées aux microtubules (métabolisme), Protéolyse (), Pyrazines (pharmacologie), Régulation de l'expression des gènes (), Régulation de l'expression des gènes (génétique), Thiophènes (pharmacologie).
- MESH :
- biosynthèse : Interleukine-8.
- génétique : Glycogen Synthase Kinase 3, I-kappa B Kinase, Interleukine-8, Lysosomes, Protéines I-kappa B, Protéines associées aux microtubules, Régulation de l'expression des gènes.
- métabolisme : Facteur de transcription NF-kappa B, Glycogen Synthase Kinase 3, I-kappa B Kinase, Lysosomes, Protéines I-kappa B, Protéines associées aux microtubules.
- pharmacologie : Acides boroniques, Antinéoplasiques, Cétones, Dipeptides, Inhibiteurs du protéasome, Leupeptines, Pyrazines, Thiophènes.
- Bortézomib, Facteurs temps, Glycogen synthase kinase 3 beta, Humains, Inhibiteur alpha de NF-KappaB, Lignée cellulaire tumorale, Mutation faux-sens, Protéolyse, Régulation de l'expression des gènes.
English descriptors
- KwdEn :
- Antineoplastic Agents (pharmacology), Boronic Acids (pharmacology), Bortezomib, Cell Line, Tumor, Dipeptides (pharmacology), Gene Expression Regulation (drug effects), Gene Expression Regulation (genetics), Glycogen Synthase Kinase 3 (genetics), Glycogen Synthase Kinase 3 (metabolism), Glycogen Synthase Kinase 3 beta, Humans, I-kappa B Kinase (genetics), I-kappa B Kinase (metabolism), I-kappa B Proteins (genetics), I-kappa B Proteins (metabolism), Interleukin-8 (biosynthesis), Interleukin-8 (genetics), Ketones (pharmacology), Leupeptins (pharmacology), Lysosomes (genetics), Lysosomes (metabolism), Microtubule-Associated Proteins (genetics), Microtubule-Associated Proteins (metabolism), Mutation, Missense, NF-KappaB Inhibitor alpha, NF-kappa B (metabolism), Proteasome Inhibitors (pharmacology), Proteolysis (drug effects), Pyrazines (pharmacology), Thiophenes (pharmacology), Time Factors.
- MESH :
- chemical , biosynthesis : Interleukin-8.
- chemical , genetics : Glycogen Synthase Kinase 3, I-kappa B Kinase, I-kappa B Proteins, Interleukin-8, Microtubule-Associated Proteins.
- chemical , metabolism : Glycogen Synthase Kinase 3, I-kappa B Kinase, I-kappa B Proteins, Microtubule-Associated Proteins, NF-kappa B.
- chemical , pharmacology : Antineoplastic Agents, Boronic Acids, Dipeptides, Ketones, Leupeptins, Proteasome Inhibitors, Pyrazines, Thiophenes.
- chemical : Bortezomib, Glycogen Synthase Kinase 3 beta, NF-KappaB Inhibitor alpha.
- drug effects : Gene Expression Regulation, Proteolysis.
- genetics : Gene Expression Regulation, Lysosomes.
- metabolism : Lysosomes.
- Cell Line, Tumor, Humans, Mutation, Missense, Time Factors.
Abstract
Proteasome inhibitors (PIs) have been reported to induce apoptosis in many types of tumor. Their apoptotic activities have been suggested to be associated with the up-regulation of molecules implicated in pro-apoptotic cascades such as p53, p21(Waf1), and p27(Kip1). Moreover, the blocking of NF-κB nuclear translocation via the stabilization of IκB is an important mechanism of PI-induced apoptosis. However, we found that long-term incubation with PIs (PS-341 or MG132) increased NF-κB-regulated gene expression such as COX-2, cIAP2, XIAP, and IL-8 in a dose- and time-dependent manner, which was mediated by phosphorylation of IκBα and its subsequent degradation via the alternative route, lysosome. Overexpression of the IκBα superrepressor (IκBα-SR) blocked PI-induced NF-κB activation. Treatment with lysosomal inhibitors (ammonium chloride or chloroquine) or inhibitors of cathepsins (Z-FF-FMK or Z-FA-FMK) or knock-down of LC3B expression by siRNAs suppressed PI-induced IκBα degradation. Furthermore, we found that both IKK-dependent and IKK-independent pathways were required for PI-induced IκBα degradation. Pretreatment with IKKβ specific inhibitor, SC-514, partially suppressed IκBα degradation and IL-8 production by PIs. Blockade of IKK activity using insolubilization by heat shock (HS) and knock-down by siRNAs for IKKβ only delayed IκBα degradation up to 8 h after treatment with PIs. In addition, PIs induced Akt-dependent inactivation of GSK-3β. Inactive GSK-3β accelerated PI-induced IκBα degradation. Overexpression of active GSK-3β (S9A) or knock-down of GSK-3β delayed PI-induced IκBα degradation. Collectively, our data demonstrate that long-term incubation with PIs activates NF-κB, which is mediated by IκBα degradation via the lysosome in an IKK-dependent and IKK-independent manner.
DOI: 10.1074/jbc.M113.480921
PubMed: 24085292
Affiliations:
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pubmed:24085292Le document en format XML
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<term>Boronic Acids (pharmacology)</term>
<term>Bortezomib</term>
<term>Cell Line, Tumor</term>
<term>Dipeptides (pharmacology)</term>
<term>Gene Expression Regulation (drug effects)</term>
<term>Gene Expression Regulation (genetics)</term>
<term>Glycogen Synthase Kinase 3 (genetics)</term>
<term>Glycogen Synthase Kinase 3 (metabolism)</term>
<term>Glycogen Synthase Kinase 3 beta</term>
<term>Humans</term>
<term>I-kappa B Kinase (genetics)</term>
<term>I-kappa B Kinase (metabolism)</term>
<term>I-kappa B Proteins (genetics)</term>
<term>I-kappa B Proteins (metabolism)</term>
<term>Interleukin-8 (biosynthesis)</term>
<term>Interleukin-8 (genetics)</term>
<term>Ketones (pharmacology)</term>
<term>Leupeptins (pharmacology)</term>
<term>Lysosomes (genetics)</term>
<term>Lysosomes (metabolism)</term>
<term>Microtubule-Associated Proteins (genetics)</term>
<term>Microtubule-Associated Proteins (metabolism)</term>
<term>Mutation, Missense</term>
<term>NF-KappaB Inhibitor alpha</term>
<term>NF-kappa B (metabolism)</term>
<term>Proteasome Inhibitors (pharmacology)</term>
<term>Proteolysis (drug effects)</term>
<term>Pyrazines (pharmacology)</term>
<term>Thiophenes (pharmacology)</term>
<term>Time Factors</term>
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<term>Antinéoplasiques (pharmacologie)</term>
<term>Bortézomib</term>
<term>Cétones (pharmacologie)</term>
<term>Dipeptides (pharmacologie)</term>
<term>Facteur de transcription NF-kappa B (métabolisme)</term>
<term>Facteurs temps</term>
<term>Glycogen Synthase Kinase 3 (génétique)</term>
<term>Glycogen Synthase Kinase 3 (métabolisme)</term>
<term>Glycogen synthase kinase 3 beta</term>
<term>Humains</term>
<term>I-kappa B Kinase (génétique)</term>
<term>I-kappa B Kinase (métabolisme)</term>
<term>Inhibiteur alpha de NF-KappaB</term>
<term>Inhibiteurs du protéasome (pharmacologie)</term>
<term>Interleukine-8 (biosynthèse)</term>
<term>Interleukine-8 (génétique)</term>
<term>Leupeptines (pharmacologie)</term>
<term>Lignée cellulaire tumorale</term>
<term>Lysosomes (génétique)</term>
<term>Lysosomes (métabolisme)</term>
<term>Mutation faux-sens</term>
<term>Protéines I-kappa B (génétique)</term>
<term>Protéines I-kappa B (métabolisme)</term>
<term>Protéines associées aux microtubules (génétique)</term>
<term>Protéines associées aux microtubules (métabolisme)</term>
<term>Protéolyse ()</term>
<term>Pyrazines (pharmacologie)</term>
<term>Régulation de l'expression des gènes ()</term>
<term>Régulation de l'expression des gènes (génétique)</term>
<term>Thiophènes (pharmacologie)</term>
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<term>I-kappa B Kinase</term>
<term>I-kappa B Proteins</term>
<term>Interleukin-8</term>
<term>Microtubule-Associated Proteins</term>
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<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Glycogen Synthase Kinase 3</term>
<term>I-kappa B Kinase</term>
<term>I-kappa B Proteins</term>
<term>Microtubule-Associated Proteins</term>
<term>NF-kappa B</term>
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<term>Boronic Acids</term>
<term>Dipeptides</term>
<term>Ketones</term>
<term>Leupeptins</term>
<term>Proteasome Inhibitors</term>
<term>Pyrazines</term>
<term>Thiophenes</term>
</keywords>
<keywords scheme="MESH" type="chemical" xml:lang="en"><term>Bortezomib</term>
<term>Glycogen Synthase Kinase 3 beta</term>
<term>NF-KappaB Inhibitor alpha</term>
</keywords>
<keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Interleukine-8</term>
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<term>Proteolysis</term>
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<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Gene Expression Regulation</term>
<term>Lysosomes</term>
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<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Glycogen Synthase Kinase 3</term>
<term>I-kappa B Kinase</term>
<term>Interleukine-8</term>
<term>Lysosomes</term>
<term>Protéines I-kappa B</term>
<term>Protéines associées aux microtubules</term>
<term>Régulation de l'expression des gènes</term>
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<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lysosomes</term>
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<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Facteur de transcription NF-kappa B</term>
<term>Glycogen Synthase Kinase 3</term>
<term>I-kappa B Kinase</term>
<term>Lysosomes</term>
<term>Protéines I-kappa B</term>
<term>Protéines associées aux microtubules</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Acides boroniques</term>
<term>Antinéoplasiques</term>
<term>Cétones</term>
<term>Dipeptides</term>
<term>Inhibiteurs du protéasome</term>
<term>Leupeptines</term>
<term>Pyrazines</term>
<term>Thiophènes</term>
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<keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term>
<term>Humans</term>
<term>Mutation, Missense</term>
<term>Time Factors</term>
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<keywords scheme="MESH" xml:lang="fr"><term>Bortézomib</term>
<term>Facteurs temps</term>
<term>Glycogen synthase kinase 3 beta</term>
<term>Humains</term>
<term>Inhibiteur alpha de NF-KappaB</term>
<term>Lignée cellulaire tumorale</term>
<term>Mutation faux-sens</term>
<term>Protéolyse</term>
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<front><div type="abstract" xml:lang="en">Proteasome inhibitors (PIs) have been reported to induce apoptosis in many types of tumor. Their apoptotic activities have been suggested to be associated with the up-regulation of molecules implicated in pro-apoptotic cascades such as p53, p21(Waf1), and p27(Kip1). Moreover, the blocking of NF-κB nuclear translocation via the stabilization of IκB is an important mechanism of PI-induced apoptosis. However, we found that long-term incubation with PIs (PS-341 or MG132) increased NF-κB-regulated gene expression such as COX-2, cIAP2, XIAP, and IL-8 in a dose- and time-dependent manner, which was mediated by phosphorylation of IκBα and its subsequent degradation via the alternative route, lysosome. Overexpression of the IκBα superrepressor (IκBα-SR) blocked PI-induced NF-κB activation. Treatment with lysosomal inhibitors (ammonium chloride or chloroquine) or inhibitors of cathepsins (Z-FF-FMK or Z-FA-FMK) or knock-down of LC3B expression by siRNAs suppressed PI-induced IκBα degradation. Furthermore, we found that both IKK-dependent and IKK-independent pathways were required for PI-induced IκBα degradation. Pretreatment with IKKβ specific inhibitor, SC-514, partially suppressed IκBα degradation and IL-8 production by PIs. Blockade of IKK activity using insolubilization by heat shock (HS) and knock-down by siRNAs for IKKβ only delayed IκBα degradation up to 8 h after treatment with PIs. In addition, PIs induced Akt-dependent inactivation of GSK-3β. Inactive GSK-3β accelerated PI-induced IκBα degradation. Overexpression of active GSK-3β (S9A) or knock-down of GSK-3β delayed PI-induced IκBα degradation. Collectively, our data demonstrate that long-term incubation with PIs activates NF-κB, which is mediated by IκBα degradation via the lysosome in an IKK-dependent and IKK-independent manner. </div>
</front>
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<affiliations><list></list>
<tree><noCountry><name sortKey="Jeong, Jiyeong" sort="Jeong, Jiyeong" uniqKey="Jeong J" first="Jiyeong" last="Jeong">Jiyeong Jeong</name>
<name sortKey="Lee, Kyoung Hee" sort="Lee, Kyoung Hee" uniqKey="Lee K" first="Kyoung-Hee" last="Lee">Kyoung-Hee Lee</name>
<name sortKey="Yoo, Chul Gyu" sort="Yoo, Chul Gyu" uniqKey="Yoo C" first="Chul-Gyu" last="Yoo">Chul-Gyu Yoo</name>
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