Reactive oxygen species-mediated activation of the Akt/ASK1/p38 signaling cascade and p21Cip1 downregulation are required for shikonin-induced apoptosis = shikonin에 의해 유도되는 세포사멸 기전에서의 AKT/ASK1/p38 신호전달 체계의 역할 규명

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dc.contributor.authorJiwon Ahn-
dc.contributor.authorMi Sun Won-
dc.contributor.authorJ H Choi-
dc.contributor.authorYong Sung Kim-
dc.contributor.authorCho-Rok Jung-
dc.contributor.authorDong-Soo Im-
dc.contributor.authorM L Kyun-
dc.contributor.authorK Lee-
dc.contributor.authorK B Song-
dc.contributor.authorKyung-Sook Chung-
dc.date.accessioned2017-04-19T09:40:14Z-
dc.date.available2017-04-19T09:40:14Z-
dc.date.issued2013-
dc.identifier.issn1360-8185-
dc.identifier.uri10.1007/s10495-013-0835-5ko
dc.identifier.urihttps://oak.kribb.re.kr/handle/201005/11344-
dc.description.abstractShikonin derivatives exert powerful cytotoxic effects, induce apoptosis and escape multidrug resistance in cancer. However, the diverse mechanisms underlying their anticancer activities are not completely understood. Here, we demonstrated that shikonin-induced apoptosis is caused by reactive oxygen species (ROS)-mediated activation of Akt/ASK1/p38 mitogen-activated protein kinase (MAPK) and downregulation of p21Cip1. In the presence of shikonin, inactivation of Akt caused apoptosis signal-regulating kinase 1 (ASK1) dephosphorylation at Ser83, which is associated with ASK1 activation. Shikonin-induced apoptosis was enhanced by inhibition of Akt, whereas overexpression of constitutively active Akt prevented apoptosis through modulating ASK1 phosphorylation. Silencing ASK1 and MKK3/6 by siRNA reduced the activation of MAPK kinases (MKK) 3/6 and p38 MAPK, and apoptosis, respectively. Antioxidant N-acetyl cysteine attenuated ASK1 dephosphorylation and p38 MAPK activation, indicating that shikonin-induced ROS is involved in the activation of Akt/ASK1/p38 pathway. Expression of p21Cip1 was significantly induced in early response, but gradually decreased by prolonged exposure to shikonin. Overexpression of p21Cip1 have kept cells longer in G1 phase and attenuated shikonin-induced apoptosis. Depletion of p21Cip1 facilitated shikonin-induced apoptosis, implying that p21Cip1 delayed shikonin-induced apoptosis via G1 arrest. Immunohistochemistry and in vitro binding assays showed transiently altered localization of p21 Cip1 to the cytoplasm by shikonin, which was blocked by Akt inhibition. The cytoplasmic p21Cip1 actually binds to and inhibits the activity of ASK1, regulating the cell cycle progression at G1. These findings suggest that shikonin-induced ROS activated ASK1 by decreasing Ser83 phosphorylation and by dissociation of the negative regulator p21 Cip1, leading to p38 MAPK activation, and finally, promoting apoptosis.-
dc.publisherSpringer-
dc.titleReactive oxygen species-mediated activation of the Akt/ASK1/p38 signaling cascade and p21Cip1 downregulation are required for shikonin-induced apoptosis = shikonin에 의해 유도되는 세포사멸 기전에서의 AKT/ASK1/p38 신호전달 체계의 역할 규명-
dc.title.alternativeReactive oxygen species-mediated activation of the Akt/ASK1/p38 signaling cascade and p21Cip1 downregulation are required for shikonin-induced apoptosis-
dc.typeArticle-
dc.citation.titleApoptosis-
dc.citation.number7-
dc.citation.endPage881-
dc.citation.startPage870-
dc.citation.volume18-
dc.contributor.affiliatedAuthorJiwon Ahn-
dc.contributor.affiliatedAuthorMi Sun Won-
dc.contributor.affiliatedAuthorYong Sung Kim-
dc.contributor.affiliatedAuthorCho-Rok Jung-
dc.contributor.affiliatedAuthorDong-Soo Im-
dc.contributor.affiliatedAuthorKyung-Sook Chung-
dc.contributor.alternativeName안지원-
dc.contributor.alternativeName원미선-
dc.contributor.alternativeName최정해-
dc.contributor.alternativeName김용성-
dc.contributor.alternativeName정초록-
dc.contributor.alternativeName임동수-
dc.contributor.alternativeName견미랑-
dc.contributor.alternativeName이경-
dc.contributor.alternativeName송경빈-
dc.contributor.alternativeName정경숙-
dc.identifier.bibliographicCitationApoptosis, vol. 18, no. 7, pp. 870-881-
dc.identifier.doi10.1007/s10495-013-0835-5-
dc.subject.keywordAkt-
dc.subject.keywordASK1-
dc.subject.keywordNegative regulator-
dc.subject.keywordp21Cip1-
dc.subject.keywordShikonin-induced apoptosis-
dc.subject.localAKT-
dc.subject.localAkt-
dc.subject.localASK1-
dc.subject.localNegative regulator-
dc.subject.localP21Cip1-
dc.subject.localp21Cip1-
dc.subject.localp21cip1-
dc.subject.localShikonin-induced apoptosis-
dc.description.journalClassY-
Appears in Collections:
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
Division of Biomedical Research > Personalized Genomic Medicine Research Center > 1. Journal Articles
Division of Research on National Challenges > 1. Journal Articles
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