Cell Fate Regulation upon DNA Damage: p53 Serine 46 Kinases Pave the Cell Death Road

Liebl, Magdalena C.; Hofmann, Thomas G.

doi:10.1002/bies.201900127

Cited by 48 publications

(40 citation statements)

References 106 publications

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“…As an unexpected result, in contrast with other tyrosine kinases receptors we observed striking activation of IGF-1R followed by Akt phosphorylation upon TA exposure in pLIVE-DCN groups. In parallel, elevated phospho-p53 levels were observed especially of that phosphorylated at serine 46 residue a marker of cell death response (72). This finding is in agreement with the publication shown that decorin can activate this receptor inducing Akt phosphorylation in renal fibroblasts and normal endothelial cells (38).…”

Section: Discussionsupporting

confidence: 90%

Protective Role of Decorin in Primary Hepatocellular Carcinoma

et al. 2020

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Hepatocellular carcinoma (HCC) represents one of the most frequent type of primary liver cancers. Decorin, a small leucine-rich proteoglycan of the extracellular matrix, represents a powerful tumor cell growth and migration inhibitor by hindering receptor tyrosine kinases and inducing p21 WAF1/CIP1. In this study, first we tested decorin expression in HCCs utilizing in silico data, as well as formalin fixed paraffin embedded tissue samples of HCC in a tissue microarray (TMA). In silico data revealed that DCN/SMA mRNA ratio is decreased in HCC compared to normal tissues and follows the staging of the disease. Among TMA samples, 52% of HCCs were decorin negative, 33% exhibited low, and 15% high decorin levels corroborating in silico results. In addition, applying conditioned media of hepatoma cells inhibited decorin expression in LX2 stellate cells in vitro. These results raise the possibility that decorin acts as a tumor suppressor in liver cancer and that is why its expression decreased in HCCs. To further test the protective role of decorin, the proteoglycan was overexpressed in a mouse model of hepatocarcinogenesis evoked by thioacetamide (TA). After transfection, the excessive proteoglycan amount was mainly detected in hepatocytes around the central veins. Upon TA-induced hepatocarcinogenesis, the highest tumor count was observed in mice with no decorin production. Decorin gene delivery reduced tumor formation, in parallel with decreased pEGFR, increased pIGF1R levels, and with concomitant induction of pAkt (T308) and phopho-p53, suggesting a novel mechanism of action. Our results suggest the idea that decorin can be utilized as an anti-cancer agent.

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Section: Discussionsupporting

confidence: 90%

Protective Role of Decorin in Primary Hepatocellular Carcinoma

et al. 2020

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“…It has been observed that phosphorylation of p53 in ser15 and ser20 occur during slight damage to DNA, while phosphorylation in ser46 is involved with cell death [37][38][39]. Phosphorylation of p53 in ser46 is related to genotoxic stress and occurs after several hours of cell damage when the cell death process could be considered irreversible, which leads to cell cycle arrest and activation of control points [39,40]. It has been seen that some natural compounds promote the phosphorylation of p53 in ser46; such is the case of the induction of cell death by an extract of Zelkova serrata, which arrests the cell cycle in S-phase, activation of caspase-8 and an increase in the amount of p-p53(ser46) in oral cancer cells in contrast to non-cancerous fibroblasts [41].…”

Section: Discussionmentioning

confidence: 99%

Tepary Bean (Phaseolus acutifolius) Lectins Induce Apoptosis and Cell Arrest in G0/G1 by P53(Ser46) Phosphorylation in Colon Cancer Cells

et al. 2020

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A Tepary bean lectin fraction (TBLF) has been studied because it exhibits differential cytotoxic and anticancer effects on colon cancer. The present work focuses on the evaluation of the apoptotic mechanism of action on colon cancer cells. Initially, lethal concentrations (LC50) were obtained for the three studied cell lines (HT-29, RKO and SW-480). HT-29 showed the highest LC50, 10 and 100 times higher than that of RKO and SW-480 cells, respectively. Apoptosis was evaluated by flow cytometry, where HT-29 cells showed the highest levels of early and total apoptosis, caspases activity was confirmed and necrosis was discarded. The effect on cell cycle arrest was shown in the G0/G1 phase. Specific apoptosis-related gene expression was determined, where an increase in p53 and a decrease in Bcl-2 were observed. Expression of p53 gene showed the maximum level at 8 h with an important decrease at 12 and 24 h, also the phosphorylated p53(ser46) increased at 8 h. Our results show that TBLF induces apoptosis in colon cancer cells by p-p53(ser46) involvement. Further studies will focus on studying the specific signal transduction pathway.

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“…This is important because tumor suppressor p53 is a sensor of DNA damages. After mild damage, p53 directs the cellular response to cell cycle arrest, DNA repair, and cell survival, whereas upon severe damage, p53 drives the cell death response (Liebl & Hofmann, 2019). In other words, AIT binding to p23 may explain the DNA damage response described in other studies, via p53.…”

Section: Discussionmentioning

confidence: 99%

Anticancer properties and mechanism of action of the quassinoid ailanthone

Bailly

2020

Phytotherapy Research

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Ailanthone (AIT) is a quassinoid natural product isolated from the worldwide‐distributed plant Ailanthus altissima. The drug displays multiple pharmacological properties, in particular significant antitumor effects against a variety of cancer cell lines in vitro. Potent in vivo activities have been evidenced in mice bearing hepatocellular carcinoma, nonsmall cell lung cancer and castration‐resistant prostate cancer. This review focusses on the mechanism of action of AIT, notably to highlight the capacity of the drug to activate DNA damage responses, to inhibit the Hsp90 co‐chaperone p23 and to modulate the expression of several microRNA. The interconnexion between these effects is discussed. The unique capacity of AIT to downregulate oncogenic miR‐21 and to upregulate the tumor suppressor miRNAs miR‐126, miR‐148a, miR‐195, and miR‐449a is presented. AIT exploits several microRNAs to exert its anticancer effects in distinct tumor types. AIT is one of the rare antitumor natural products that binds to and strongly inhibits cochaperone p23, opening interesting perspectives to treat cancers. However, the toxicity profile of the molecule may limit its development as an anticancer drug, unless it can be properly formulated to prevent AIT‐induced gastro‐intestinal damages in particular. The antitumor properties of AIT and analogs are underlined, with the aim to encourage further pharmacological studies with this underexplored natural product and related quassinoids. Highlights Ailanthone (AIT) is an anticancer quassinoid isolated from Ailanthus altissima It inhibits proliferation and induces cell death of many cancer cell types The drug activates DNA damage response and targets p23 cochaperone Up or downregulation of several microRNA by AIT contributes to the anticancer activity Analogs or specific formulations must be developed to prevent the toxicity of AIT

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Cell Fate Regulation upon DNA Damage: p53 Serine 46 Kinases Pave the Cell Death Road

Cited by 48 publications

References 106 publications

Protective Role of Decorin in Primary Hepatocellular Carcinoma

Protective Role of Decorin in Primary Hepatocellular Carcinoma

Tepary Bean (Phaseolus acutifolius) Lectins Induce Apoptosis and Cell Arrest in G0/G1 by P53(Ser46) Phosphorylation in Colon Cancer Cells

Anticancer properties and mechanism of action of the quassinoid ailanthone

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