Salvation of the fallen angel: Reactivating mutant p53

Yang, Li; Wang, Zhuoyi; Chen, Yu‐Chen; Petersen, Robert B.; Zheng, Ling; Huang, Kun

doi:10.1111/bph.14572

Cited by 27 publications

(23 citation statements)

References 142 publications

(167 reference statements)

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“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMA-COLOGY (Harding et al, 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander, Cidilowski et al, 2019;Alexander, Fabbro et al, 2019;.…”

Section: Nomenclature Of Targets and Ligandsmentioning

confidence: 99%

The constitutive androstane receptor and pregnane X receptor in the brain

Torres-Vergara

Espinoza

et al. 2020

British J Pharmacology

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Since their discovery, the orphan nuclear receptors constitutive androstane receptor (CAR;NR1I3) and pregnane X receptor (PXR;NR1I2) have been regarded as master regulators of drug disposition and detoxification mechanisms. They regulate the metabolism and transport of endogenous mediators and xenobiotics in organs including the liver, intestine and brain. However, with proposals of new physiological functions for NR1I3 and NR1I2, there is increasing interest in the role of these receptors in influencing brain function. This review will summarise key findings regarding the expression and function of NR1I3 and NR1I2 in the brain, hereby highlighting the need for further research in this field.

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Section: Nomenclature Of Targets and Ligandsmentioning

confidence: 99%

The constitutive androstane receptor and pregnane X receptor in the brain

Torres-Vergara

Espinoza

et al. 2020

British J Pharmacology

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“…Transcription factor p53 plays an important role in preventing tumorigenesis and tumor progression [34]. Downregulation of phospho-p53 (Ser15) expression predicted poor prognosis in patients with colorectal carcinoma [35].…”

Section: Discussionmentioning

confidence: 99%

Cystathionine-β-synthase affects organization of cytoskeleton and modulates carcinogenesis in colorectal carcinoma cells

Lišková

Chovancova

Babula

et al. 2020

Preprint

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Background: Cystathionine-b-synthase (CBS), one of three enzymes that endogenously produce hydrogen sulfide, is extensively studied for its relevance also in various tumor’s cell. In our previous work we observed that immunofluorescence pattern of CBS is very similar to that from tubulin and actin. Therefore, we focused on potential interaction of CBS with cytoskeletal proteins b-actin and b-tubulin and functional relevance of the potential interaction of these proteins in colorectal carcinoma cell lines.Methods: To study potential interaction of CBS with cytoskeletal proteins and its functional consequences, CBS-knockout DLD1 (DLDx) cell line was established by using the CRISPR/Cas9 gene editing method. Interaction of selected cytoskeletal protein with CBS was studied by immunoprecipitation and Western blot analysis, immunofluorescence and proximity ligation assay. Functional consequences were studied by proliferation and migration assays and by generation of xenografts in SCID/bg mice.Results: We have found that CBS, an enzyme that endogenously produces H2S, binds to cytoskeletal b-tubulin and to lesser extent also to b-actin in colorectal carcinoma derived cells. When CBS was knockouted by CRISPR/Cas9 technique (DLDx), we observed de-arranged cytoskeleton compared to unmodified DLD1 cell line. Treatment of these cells with a slow sulfide donor GYY4137 resulted in normal organization of cytoskeleton, thus pointing to the role of CBS in microtubule dynamics. To evaluate the physiological importance of this observation, both DLD1 and DLDx cells were injected into SCID/bg mice and size/mass of developed xenografts was evaluated. Significantly larger tumors developed from DLDx compared to DLD1 cells, which correlated with increased proliferation of these cells. Conclusions: Taken together, in colorectal cancer DLD1 cells, CBS binds to cytoskeleton, modulates microtubule dynamics and thus affects the proliferation and migration in colorectal carcinoma stable cell line.

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“…A large number of drug candidates, including small molecules or chemotherapeutic agents, have been identified or designed to rescue mutant p53 and reactivate its antitumor capacity through various mechanisms. For example, PRIMA-1 can restore active conformation of mutant p53 and PK7088 can upregulate p21 expression and apoptotic functions (7,17). In the present study, CP-31398, a stabilizing agent that restores the wild-type conformation of mutated p53 protein (18), was used to improve the chemotherapeutic efficacy of sorafenib for p53-mutated ATC cells.…”

Section: Introductionmentioning

confidence: 93%

“…Loss of p53 function has been reported to result in poorly differentiated thyroid tumors (6). Hence, mutant p53 protein can be considered a crucial therapeutic target in patients with ATC (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Potential synergistic effects of sorafenib and CP‑31398 for treating anaplastic thyroid cancer with p53 mutations

Lin

Huang

et al. 2020

Oncol Lett

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Thyroid cancer is the most commonly diagnosed endocrine cancer. Anaplastic thyroid cancer (ATC) is the most aggressive type of thyroid cancer and has a poor prognosis. Loss of p53 function has been reported to lead to poorly differentiated thyroid tumors; therefore, mutant p53 protein can be considered a crucial therapeutic target in patients with ATC. Sorafenib, a multi-kinase inhibitor, has been approved for the treatment of metastatic and differentiated thyroid cancer. Combined targeted therapy, including sorafenib, may be clinically significant for patients with ATC harboring p53 mutations. In the present study, CP-31398, a p53-restoring agent, was used to improve the therapeutic efficacy of sorafenib in SW579 cells, an ATC cell line harboring p53 mutations. The molecular function of CP-31398 was evaluated using western blot analysis and a luciferase reporter assay. The decreased viability of SW579 cells, following CP-31398 treatment, was augmented by sorafenib, and CP-31398 enhanced the antimitogenic effect of sorafenib; thus, sorafenib and CP-31398 synergistically inhibited the growth of SW579 cells. These results indicate a potential clinical application of CP-31398 for patients with ATC harboring p53 abnormalities, since these individuals generally respond poorly to sorafenib alone.

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Salvation of the fallen angel: Reactivating mutant p53

Cited by 27 publications

References 142 publications

The constitutive androstane receptor and pregnane X receptor in the brain

The constitutive androstane receptor and pregnane X receptor in the brain

Cystathionine-β-synthase affects organization of cytoskeleton and modulates carcinogenesis in colorectal carcinoma cells

Potential synergistic effects of sorafenib and CP‑31398 for treating anaplastic thyroid cancer with p53 mutations

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