Buxus alkaloid compound destabilizes mutant p53 through inhibition of the HSF1 chaperone axis
Wang Yu-Ling1; Wu Wei1; Su Yong-Nan1; Ai Zhi-Peng1; Mou Han-Chuan1; Wan Luo-Sheng2; Luo Ying1; Qiu Ming-Hua2; Zhang Ji-Hong1
Corresponding AuthorQiu Ming-Hua(mhchiu@mail.kib.ac.cn) ; Zhang Ji-Hong(zhjihong2000@kust.edu.cn)
Source PublicationPHYTOMEDICINE
AbstractBackground: P53 is the most frequently mutated gene in most tumour types, and the mutant p53 protein accumulates at high levels in tumours to promote tumour development and progression. Thus, targeting mutant p53 for degradation is one of the therapeutic strategies used to manage tumours that depend on mutant p53 for survival. Buxus alkaloids are traditionally used in the treatment of cardiovascular diseases. We found that triterpenoid alkaloids extracted from Buxus sinica found in the Yunnan Province exhibit anticancer activity by depleting mutant p53 levels in colon cancer cells. Purpose: To explore the anticancer mechanism of action of the triterpenoid alkaloid KBA01 compound by targeting mutant p53 degradation. Study design and methods: Different mutant p53 cell lines were used to evaluate the anticancer activity of KBA01. MTT assay, colony formation assay and cell cycle analysis were performed to examine the effect of KBA01 on cancer cell proliferation. Western blotting and qPCR were used to investigate effects of depleting mutant p53, and a ubiquitination assay was used to determine mutant p53 ubiquitin levels after cells were treated with the compound. Co-IP and small interfering RNA assays were used to explore the effects of KBA01 on the interaction of Hsp90 with mutant p53. Results: The triterpenoid alkaloid KBA01 can induce G2/M cell cycle arrest and the apoptosis of HT29 colon cancer cells. KBA01 decreases the stability of DNA contact mutant p53 proteins through the proteasomal pathway with minimal effects on p53 mutant protein conformation. Moreover, KBA01 enhances the interaction of mutant p53 with Hsp70, CHIP and MDM2, and knocking down CHIP and MDM2 stabilizes mutant p53 levels in KBA01-treated cells. In addition, KBA01 disrupts the HSF1-mutant p53-Hsp90 complex and releases mutant p53 to enable its MDM2- and CHIP-mediated degradation. Conclusion: Our study reveals that KBA01 depletes mutant p53 protein in a chaperone-assisted ubiquitin/proteasome degradation pathway in cancer cells, providing insights into potential strategies to target mutant p53 tumours.
KeywordBuxus alkaloid Cancer Ubiquitination Mutant p53 HSF1
Indexed BySCI ; SCI
WOS Research AreaPlant Sciences ; Pharmacology & Pharmacy ; Integrative & Complementary Medicine
WOS SubjectPlant Sciences ; Chemistry, Medicinal ; Integrative & Complementary Medicine ; Pharmacology & Pharmacy
WOS IDWOS:000525848500021
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Document Type期刊论文
Corresponding AuthorQiu Ming-Hua; Zhang Ji-Hong
Affiliation1.Kunming Univ Sci & Technol, Med Sch, Kunming 650500, Yunnan, Peoples R China
2.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650201, Yunnan, Peoples R China
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GB/T 7714
Wang Yu-Ling,Wu Wei,Su Yong-Nan,et al. Buxus alkaloid compound destabilizes mutant p53 through inhibition of the HSF1 chaperone axis[J]. PHYTOMEDICINE,2020,68:12.
APA Wang Yu-Ling.,Wu Wei.,Su Yong-Nan.,Ai Zhi-Peng.,Mou Han-Chuan.,...&Zhang Ji-Hong.(2020).Buxus alkaloid compound destabilizes mutant p53 through inhibition of the HSF1 chaperone axis.PHYTOMEDICINE,68,12.
MLA Wang Yu-Ling,et al."Buxus alkaloid compound destabilizes mutant p53 through inhibition of the HSF1 chaperone axis".PHYTOMEDICINE 68(2020):12.
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