AMP-activated protein kinase (AMPK)/Ulk1-dependent autophagic pathway contributes to C6 ceramide-induced cytotoxic effects in cultured colorectal cancer HT-29 cells
Identifieur interne : 001252 ( Main/Exploration ); précédent : 001251; suivant : 001253AMP-activated protein kinase (AMPK)/Ulk1-dependent autophagic pathway contributes to C6 ceramide-induced cytotoxic effects in cultured colorectal cancer HT-29 cells
Auteurs : Hai-Zhong Huo [République populaire de Chine] ; Bing Wang [République populaire de Chine] ; Jian Qin [République populaire de Chine] ; Shan-Yu Guo [République populaire de Chine] ; Wen-Yong Liu [République populaire de Chine] ; Yan Gu [République populaire de Chine]Source :
- Molecular and Cellular Biochemistry [ 0300-8177 ] ; 2013-06-01.
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Abstract
Abstract: Colorectal cancer is the second leading cause of cancer-related deaths. Drug resistance and/or off-target toxicity against normal cells limit the effectiveness of current chemotherapies for the treatment of colorectal cancer. In the current study, we studied the potential cytotoxic effects of short-chain and cell-permeable C6 ceramide in cultured colorectal cancer HT-29 cells and focused on the underlying mechanisms. We observed that C6 ceramide-induced HT-29 cell death and growth inhibition in a dose- and time-dependent manner. However, no significant apoptosis was observed in C6 ceramide-treated HT-29 cells. Our data support that autophagy contributed to C6 ceramide-induced cytotoxic effects, as autophagy inhibitors, 3-methyladenine (3-MA) and hydroxychloroquine, inhibited C6 ceramide’s effect; however, autophagy activators, everolimus (RAD001) and temsirolimus, mimicked C6 ceramide effects and induced HT-29 cell death. Further, we indentified that AMP-activated protein kinase (AMPK)/Ulk1 signaling was required for autophagy induction by C6 ceramide, and AMPK silencing by a specific short hairpin RNA suppressed C6 ceramide-induced autophagy and cytotoxic effects. Reversely, forced activation of AMPK by its activator AICAR or by genetic manipulation caused autophagic death in HT-29 cells, which was inhibited by 3-MA. Our results suggest that autophagy, but not apoptosis, is a major contributor for C6 ceramide-induced cytotoxic effects in HT-29 cells, and activation of AMPK/Ulk1 is required for the process.
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DOI: 10.1007/s11010-013-1608-8
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pathway</term><term>Autophagy</term><term>C6 ceramide</term><term>Colorectal cancer</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: Colorectal cancer is the second leading cause of cancer-related deaths. Drug resistance and/or off-target toxicity against normal cells limit the effectiveness of current chemotherapies for the treatment of colorectal cancer. In the current study, we studied the potential cytotoxic effects of short-chain and cell-permeable C6 ceramide in cultured colorectal cancer HT-29 cells and focused on the underlying mechanisms. We observed that C6 ceramide-induced HT-29 cell death and growth inhibition in a dose- and time-dependent manner. However, no significant apoptosis was observed in C6 ceramide-treated HT-29 cells. Our data support that autophagy contributed to C6 ceramide-induced cytotoxic effects, as autophagy inhibitors, 3-methyladenine (3-MA) and hydroxychloroquine, inhibited C6 ceramide’s effect; however, autophagy activators, everolimus (RAD001) and temsirolimus, mimicked C6 ceramide effects and induced HT-29 cell death. Further, we indentified that AMP-activated protein kinase (AMPK)/Ulk1 signaling was required for autophagy induction by C6 ceramide, and AMPK silencing by a specific short hairpin RNA suppressed C6 ceramide-induced autophagy and cytotoxic effects. Reversely, forced activation of AMPK by its activator AICAR or by genetic manipulation caused autophagic death in HT-29 cells, which was inhibited by 3-MA. Our results suggest that autophagy, but not apoptosis, is a major contributor for C6 ceramide-induced cytotoxic effects in HT-29 cells, and activation of AMPK/Ulk1 is required for the process.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Huo, Hai Zhong" sort="Huo, Hai Zhong" uniqKey="Huo H" first="Hai-Zhong" last="Huo">Hai-Zhong Huo</name></noRegion><name sortKey="Gu, Yan" sort="Gu, Yan" uniqKey="Gu Y" first="Yan" last="Gu">Yan Gu</name><name sortKey="Guo, Shan Yu" sort="Guo, Shan Yu" uniqKey="Guo S" first="Shan-Yu" last="Guo">Shan-Yu Guo</name><name sortKey="Liu, Wen Yong" sort="Liu, Wen Yong" uniqKey="Liu W" first="Wen-Yong" last="Liu">Wen-Yong Liu</name><name sortKey="Qin, Jian" sort="Qin, Jian" uniqKey="Qin J" first="Jian" last="Qin">Jian Qin</name><name sortKey="Wang, Bing" sort="Wang, Bing" uniqKey="Wang B" first="Bing" last="Wang">Bing Wang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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