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Shikonin promotes ubiquitination and degradation of cIAP1/2-mediated apoptosis and necrosis in triple negative breast cancer cells
Wang,Anqi1,2; Liu,Jiayu3; Yang,Yuhan2,4; Chen,Zhejie2; Gao,Caifang2; Wang,Zhanguo1; Fu,Chaomei4; Zou,Liang5; Wang,Shengpeng2
2021-12-01
Source PublicationChinese Medicine (United Kingdom)
Volume16Issue:1
Abstract

Background: Shikonin (SKO) is a natural naphthoquinone derived from Chinese herbal medicine Arnebiae Radix with high development potentials due to its anti-inflammatory and anti-tumor activities. Overwhelming evidences have indicated that SKO can induce both necrosis and apoptosis in cancer cells, while the mechanisms for triple negative breast cancer cells is still need to be disclosed. Methods: In this study, kinds of molecular biological technologies, including flow-cytometry, Western blot, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA) as well as real-time quantitative PCR (RT-qPCR), were applied for investigation on the underlying mechanisms of SKO induced necrosis and apoptosis for MDA-MB-231 cells. Inhibitors were also used for validation ofthe key signaling pathways involved in SKO triggered necrosis and apoptosis. Results: We found that SKO significantly triggered necrosis and apoptosis of MDA-MB-231 cells in both a concentration- and time-dependent manner. Mechanism studies demonstrated that SKO significantly promoted the autoubiquitination levels and facilitated the proteasome dependent degradation of cellular inhibitor of apoptosis protein 1 (cIAP1) and cIAP2 in MDA-MB-231 cells. Autoubiquitination and degradation of cIAP1 and cIAP2 induced by SKO further led to significant decreased ubiquitination and inactivation of RIP1, which played an important role in inhibition of pro-survival and accelerating of necrosis of MDA-MB-231 cells. Treatment with proteasome inhibitor lactacystin significantly rescued the cell viability induced by treatment of SKO. Conclusions: Our results demonstrate that SKO promotes the autoubiquitination and degradation of cIAP1 and cIAP2, which further induces the decrease of the ubiquitination of RIP1 to inhibit the activation of pro-survival signaling pathways and accelerate the necrosis of MDA-MB-231 cells. The disclosed mechanisms of SKO induced necrosis and apoptosis in our study is firstly reported, and it is believed that SKO could be considered as a potential candidate and further developed for the treatment of triple negative breast cancer.

KeywordApoptosis Breast Cancer Necrosis Shikonin Ubiquitination
DOI10.1186/s13020-021-00426-1
URLView the original
Indexed BySCIE
WOS Research AreaIntegrative & Complementary Medicine ; Pharmacology & Pharmacy
WOS SubjectIntegrative & Complementary Medicine ; Pharmacology & Pharmacy
WOS IDWOS:000613709100001
Scopus ID2-s2.0-85100096524
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Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorWang,Shengpeng
Affiliation1.School of medicine,Chengdu University,Chengdu,610106,China
2.State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macau,Macao
3.Clinical drug development,School of Medicine and Dentistry,Queen Mary University of London,London,United Kingdom
4.School of Pharmacy,State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China,Chengdu University of Traditional Chinese Medicine,Chengdu,611137,China
5.Key Laboratory of Coarse Cereal Processing,Ministry of Agriculture and Rural Affairs,Chengdu University,Chengdu,610106,China
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Wang,Anqi,Liu,Jiayu,Yang,Yuhan,et al. Shikonin promotes ubiquitination and degradation of cIAP1/2-mediated apoptosis and necrosis in triple negative breast cancer cells[J]. Chinese Medicine (United Kingdom),2021,16(1).
APA Wang,Anqi,Liu,Jiayu,Yang,Yuhan,Chen,Zhejie,Gao,Caifang,Wang,Zhanguo,Fu,Chaomei,Zou,Liang,&Wang,Shengpeng.(2021).Shikonin promotes ubiquitination and degradation of cIAP1/2-mediated apoptosis and necrosis in triple negative breast cancer cells.Chinese Medicine (United Kingdom),16(1).
MLA Wang,Anqi,et al."Shikonin promotes ubiquitination and degradation of cIAP1/2-mediated apoptosis and necrosis in triple negative breast cancer cells".Chinese Medicine (United Kingdom) 16.1(2021).
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