Buxus alkaloid compound destabilizes mutant p53 through inhibition of the HSF1 chaperone axis

Wang, Yuling; Wu, Wei; Su, Yongnan; Ai, Zhipeng; Mou, Han-Chuan; Wan, Luo-Sheng; Luo, Ying; Qiu, Ming‐Hua; Zhang, Jihong

doi:10.1016/j.phymed.2020.153187

Cited by 9 publications

(2 citation statements)

References 44 publications

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“…KBA01 is a natural compound of alkaloid origin from boxwood that releases mutant p53 from the protein complex by inhibiting Hsp90 activity while destabilizing the HSF1-mutant p53-Hsp90 complex. This process results in enhanced interaction of mutant p53 with MDM2 and CHIP, promoting ubiquitination and proteasomal degradation of mutant p53 ( Wang et al, 2020 ).…”

Section: Mutant P53 Stabilization and Strategies To Destabilizementioning

confidence: 99%

Targeting mutant p53 stabilization for cancer therapy

et al. 2023

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Over 50% cancer bears TP53 mutation, the highly stabilized mutant p53 protein drives the tumorigenesis and progression. Mutation of p53 not only cause loss-of-function and dominant-negative effects (DNE), but also results in the abnormal stability by the regulation of the ubiquitin-proteasome system and molecular chaperones that promote tumorigenesis through gain-of-function effects. The accumulation of mutant p53 is mainly regulated by molecular chaperones, including Hsp40, Hsp70, Hsp90 and other biomolecules such as TRIM21, BAG2 and Stat3. In addition, mutant p53 forms prion-like aggregates or complexes with other protein molecules and result in the accumulation of mutant p53 in tumor cells. Depleting mutant p53 has become one of the strategies to target mutant p53. This review will focus on the mechanism of mutant p53 stabilization and discuss how the strategies to manipulate these interconnected processes for cancer therapy.

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Section: Mutant P53 Stabilization and Strategies To Destabilizementioning

confidence: 99%

Targeting mutant p53 stabilization for cancer therapy

et al. 2023

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“…One of the first works on this subject reported that acetonic extract of BS was provided in vitro with antitumor activity against breast cancer through induction of autophagic cell death and apoptosis ( Ait-Mohamed et al, 2011 ). More recent papers focused on cyclovirobuxine D, a steroidal alkaloid present in various species of boxwood including BS for which antitumor activity was reported against several neoplasms including breast, lung and colorectal cancers, hepatocellular carcinoma and glioblastoma multiforme ( Jiang et al, 2020 ; Wang et al, 2020 ; Zhang et al, 2020 ; Zhou et al, 2020 ; Zeng et al, 2021 ). Such steroidal alkaloid appeared to act on different signalling pathways also regulating apoptosis and cell proliferation and migration.…”

Section: Introductionmentioning

confidence: 99%

Hydroalcoholic extract of Buxus sempervirens shows antiproliferative effect on melanoma, colorectal carcinoma and prostate cancer cells by affecting the autophagic flow

Volpe

Carmignani²,

Cesare³

2023

Front. Pharmacol.

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Buxus sempervirens (European Box, Buxaceae, boxwood) has been used in folk medicine to treat rheumatism, arthritis, fever, malaria and skin ulceration while, in recent years, interest has grown on possible employment of boxwood extracts in cancer therapy. We studied the effect of hydroalcoholic extract from dried leaves of Buxus sempervirens (BSHE) on four human cell lines (BMel melanoma cells, HCT116 colorectal carcinoma cells, PC3 prostate cancer cells, and HS27 skin fibroblasts) to ascertain its possible antineoplastic activity. This extract inhibited proliferation of all cell lines in different degree as shown, after 48 h-exposure and MTS assay, by the values of GR50 (normalized growth rate inhibition50) that were 72, 48, 38, and 32 μg/mL for HS27, HCT116, PC3 and BMel cells, respectively. At the above GR50 concentrations, 99% of all studied cells remained vital showing accumulation of acidic vesicles in the cytoplasm, mainly around nuclei, whereas a higher extract concentration (125 μg/mL) was cytotoxic causing, after 48 h-exposure, death of all BMel and HCT116 cells. Immunofluorescence showed microtubule-associated light chain three protein (LC3, a marker for autophagy) to be localized on the above acidic vesicles when cells were treated for 48 h with BSHE (GR50 concentrations). Western blot analysis revealed, in all treated cells, a significant increase (2.2–3.3 times at 24 h) of LC3II, i.e., the phosphatidylethanolamine conjugate of the cytoplasmic form LC3I that is recruited in autophagosome membranes during autophagy. Such increase was accompanied, in all cell lines treated for 24 h or 48 h with BSHE, by a significant increment (2.5–3.4 times at 24 h) of p62, an autophagic cargo protein undergoing degradation during the autophagic process. Therefore, BSHE appeared to promote autophagic flow with its following blockade and consequent accumulation of autophagosome or autolysosomes. The antiproliferative effects of BSHE also involved cell cycle regulators such as p21 (HS27, BMel and HCT116 cells) and cyclin B1 (HCT116, BMel and PC3 cells) whereas, among apoptosis markers, BSHE only decreased (30%–40% at 48 h) the expression of the antiapoptotic protein survivin. It was concluded that BSHE impairs autophagic flow with arrest of proliferation and death in both fibroblasts and cancer cells, being the latter much more sensitive to these effects.

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Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy

Song,

Yang,

Zhang

2024

Cancer Communications

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Cancer is a leading cause of death worldwide. Targeted therapies aimed at key oncogenic driver mutations in combination with chemotherapy and radiotherapy as well as immunotherapy have benefited cancer patients considerably. Tumor protein p53 (TP53), a crucial tumor suppressor gene encoding p53, regulates numerous downstream genes and cellular phenotypes in response to various stressors. The affected genes are involved in diverse processes, including cell cycle arrest, DNA repair, cellular senescence, metabolic homeostasis, apoptosis, and autophagy. However, accumulating recent studies have continued to reveal novel and unexpected functions of p53 in governing the fate of tumors, for example, functions in ferroptosis, immunity, the tumor microenvironment and microbiome metabolism. Among the possibilities, the evolutionary plasticity of p53 is the most controversial, partially due to the dizzying array of biological functions that have been attributed to different regulatory mechanisms of p53 signaling. Nearly 40 years after its discovery, this key tumor suppressor remains somewhat enigmatic. The intricate and diverse functions of p53 in regulating cell fate during cancer treatment are only the tip of the iceberg with respect to its equally complicated structural biology, which has been painstakingly revealed. Additionally, TP53 mutation is one of the most significant genetic alterations in cancer, contributing to rapid cancer cell growth and tumor progression. Here, we summarized recent advances that implicate altered p53 in modulating the response to various cancer therapies, including chemotherapy, radiotherapy, and immunotherapy. Furthermore, we also discussed potential strategies for targeting p53 as a therapeutic option for cancer.

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Buxus alkaloid compound destabilizes mutant p53 through inhibition of the HSF1 chaperone axis

Cited by 9 publications

References 44 publications

Targeting mutant p53 stabilization for cancer therapy

Targeting mutant p53 stabilization for cancer therapy

Hydroalcoholic extract of Buxus sempervirens shows antiproliferative effect on melanoma, colorectal carcinoma and prostate cancer cells by affecting the autophagic flow

Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy

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