Cucurbitacin induces autophagy through mitochondrial ROS production which counteracts to limit caspase-dependent apoptosis
Targeted disruption of STAT3 function has proven to be a useful cancer therapeutic approach by inducing apoptotic cell death. Cucurbitacin is currently under development as a small molecule of STAT3 inhibitor to trigger cell death in many cancers. Here, we systematically studied the molecular mechanisms underlying cucurbitacin-induced cell death, in particular the involvement of autophagy. Treatment with cucurbitacin resulted in non-apoptotic cell death in a caspase-independent manner. Notably, cucurbitacin enhanced excessive conversion of lipidated LC3 (LC3-II) and accumulation of autophagosomes in many cell types. Such autophagy and cell death induced by cucurbitacin were independent of its ability to inhibit STAT3 function, but mainly mediated by enhanced production of mitochondrial-derived reactive oxygen species (ROS), and subsequently activation of extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK). Interestingly, both the autophagy inhibitor wortmannin and knockdown of Atg5 or Beclin 1 failed to rescue the cells from cucurbitacin-induced cell death, as suppression of autophagy induced the mode of cell death to shift from autophagic cell death to caspase-dependent apoptosis. Thus the present study provides new insights into the molecular mechanisms underlying cucurbitacin-mediated cell death and supports cucurbitacin as a potential anti-cancer drug through modulating the balance between autophagic and apoptotic modes of cell death.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2012 |
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| Erschienen: |
2012 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
Autophagy - 8(2012), 4 vom: 09. Apr., Seite 559-76 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Tiejun [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.11.2012 Date Revised 08.04.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.4161/auto.18867 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM216423201 |
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| 245 | 1 | 0 | |a Cucurbitacin induces autophagy through mitochondrial ROS production which counteracts to limit caspase-dependent apoptosis |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Targeted disruption of STAT3 function has proven to be a useful cancer therapeutic approach by inducing apoptotic cell death. Cucurbitacin is currently under development as a small molecule of STAT3 inhibitor to trigger cell death in many cancers. Here, we systematically studied the molecular mechanisms underlying cucurbitacin-induced cell death, in particular the involvement of autophagy. Treatment with cucurbitacin resulted in non-apoptotic cell death in a caspase-independent manner. Notably, cucurbitacin enhanced excessive conversion of lipidated LC3 (LC3-II) and accumulation of autophagosomes in many cell types. Such autophagy and cell death induced by cucurbitacin were independent of its ability to inhibit STAT3 function, but mainly mediated by enhanced production of mitochondrial-derived reactive oxygen species (ROS), and subsequently activation of extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK). Interestingly, both the autophagy inhibitor wortmannin and knockdown of Atg5 or Beclin 1 failed to rescue the cells from cucurbitacin-induced cell death, as suppression of autophagy induced the mode of cell death to shift from autophagic cell death to caspase-dependent apoptosis. Thus the present study provides new insights into the molecular mechanisms underlying cucurbitacin-mediated cell death and supports cucurbitacin as a potential anti-cancer drug through modulating the balance between autophagic and apoptotic modes of cell death | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a 5-(6'-triphenylphosphoniumhexyl)-5,6-dihydro-6-phenyl-3,8-phenanthridinediammine |2 NLM | |
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| 700 | 1 | |a Park, Kyeong Ah |e verfasserin |4 aut | |
| 700 | 1 | |a Byun, Hee Sun |e verfasserin |4 aut | |
| 700 | 1 | |a Won, Minho |e verfasserin |4 aut | |
| 700 | 1 | |a Jeon, Juhee |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Yoonjung |e verfasserin |4 aut | |
| 700 | 1 | |a Seok, Jeong Ho |e verfasserin |4 aut | |
| 700 | 1 | |a Choi, Seung-Won |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Sang-Hee |e verfasserin |4 aut | |
| 700 | 1 | |a Man Kim, Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Ji Hoon |e verfasserin |4 aut | |
| 700 | 1 | |a Son, Chang Gue |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Zee-Won |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Han-Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Hur, Gang Min |e verfasserin |4 aut | |
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