Targeting Post-Translational Regulation of p53 in Colorectal Cancer by Exploiting Vulnerabilities in the p53-MDM2 Axis

Lai, Chih‐Ming; Xie, Cindy; Raufman, Jean‐Pierre; Xie, Guofeng

doi:10.3390/cancers14010219

Cited by 5 publications

(3 citation statements)

References 117 publications

(133 reference statements)

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“…We note that variations on E17 in human p53 are cancer mutants, frequently associated with female genital cancers ( Petitjean et al 2007 ; Ganguly and Chen 2015 ). The K24N mutation found in colorectal cancers, is thought to implicate ubiquitination by TRAF6, thereby facilitating p53 acetylation by p300 ( Lai et al 2022 ). Isothermal titration calorimetry measurements demonstrated that this structural variation did not prevent the binding affinity for p53TAD–MDM2 ( Zhan et al 2013 ).…”

Section: Discussionmentioning

confidence: 99%

The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer

Padariya

Jooste

Hupp

et al. 2022

Molecular Biology and Evolution

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The p53 tumour suppressor is a transcription factor with roles in cell development, apoptosis, oncogenesis, ageing and homeostasis in response to stresses and infections. p53 is tightly regulated by the MDM2 E3 ubiquitin ligase. The p53-MDM2 pathway has co-evolved, with MDM2 remaining largely conserved while the TP53 gene morphed into various isoforms. Studies on pre-vertebrate ancestral homologues revealed the transition from an environmentally-induced mechanism activating p53 to a tightly regulated system involving cell signaling. The evolution of this mechanism depends on structural changes in the interacting protein motifs. Elephants such as Loxodonta africana constitute ideal models to investigate this co-evolution as they are large and long-living as well as having 20 copies of TP53 isoformic sequences expressing a variety of BOX-I MDM2-binding motifs. Collectively, these isoforms would enhance sensitivity to cellular stresses, such as DNA damage, presumably accounting for strong cancer defenses and other adaptations favouring healthy ageing. Here we investigate the molecular evolution of the p53-MDM2 system by combining in silico modelling and in vitro assays to explore structural and functional aspects of p53 isoforms retaining the MDM2 interaction while forming distinct pools of cell-signalling. The methodology used demonstrates, for the first time, that in silico docking simulations can be used to explore functional aspects of elephant p53 isoforms. Our observations elucidate structural and mechanistic aspects of p53 regulation, facilitate understanding of complex cell signalling and suggest testable hypotheses of p53 evolution referencing Peto’s Paradox.

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Section: Discussionmentioning

confidence: 99%

The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer

Padariya

Jooste

Hupp

et al. 2022

Molecular Biology and Evolution

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“…MDM2, a key downstream protein of Akt, can be phosphorylated by p-Akt. p-MDM2 can translocate to the nucleus and modulate p53 levels by targeting p53 for protein degradation ( 42 ). Therefore, the Akt/MDM2/p53 signaling pathway serves a key role in regulation of the cell cycle, proliferation and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Anticancer effect of involucrasin A on colorectal cancer cells by modulating the Akt/MDM2/p53 pathway

Wei

Shen

et al. 2023

Oncol Lett

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Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide; however, there is still a lack of effective clinical anti-CRC agents. Naturally-occurring compounds have been considered a potentially valuable source of new antitumorigenic agents. Involucrasin A, a novel natural molecule, was isolated from Shuteria involucrata (Wall.) Wight & Arn by our team. In the present study, the anticancer activity of involucrasin A in HCT-116 CRC cells was evaluated. Firstly, the anti-proliferative effect of involucrasin A on HCT-116 cells was analyzed by sulforhodamine B and colony formation assays. The results revealed that involucrasin A exhibited a potent inhibitory effect on HCT-116 CRC cell proliferation in vitro. Subsequently, flow cytometry and western blotting indicated that involucrasin A induced apoptosis and upregulated the expression levels of apoptosis-related proteins, such as cleaved-caspase 6 and cleaved-caspase 9, in a dose-dependent manner. Mechanistically, involucrasin A significantly inhibited the phosphorylation of Akt and murine double minute 2 homologue (MDM2), which resulted in increased intracellular levels of p53. This was reversed by exogenous expression of the constitutively active form of Akt. Similarly, either knocking out p53 or knocking down Bax abrogated involucrasin A-induced proliferation inhibition and apoptosis. Together, the present study indicated that involucrasin A exerts antitumorigenic activities via modulating the Akt/MDM2/p53 pathway in HCT-116 CRC cells, and it is worthy of further exploration in preclinical and clinical trials.

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“…Global data show that colorectal cancer (CRC) has the third highest incidence, followed by breast and lung cancer 1 . CRC can occur as small, benign polyps inside the colon, which subsequently become malignant 2 .…”

Section: Introductionmentioning

confidence: 99%

Aspirin prevents colorectal cancer by regulating the abundance of Enterococcus cecorum and TIGIT+Treg cells

Yang,

Yan,

Wang

et al. 2024

Sci Rep

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Although aspirin can reduce the incidence of colorectal cancer (CRC), there is still uncertainty about its significance as a treatment for CRC, and the mechanism of aspirin in CRC is not well understood. In this study, we used aspirin to prevent AOM/DSS-induced CRC in mice, and the anti-CRC efficacy of aspirin was assessed using haematoxylin and eosin (H&E) staining and by determining the mouse survival rate and tumour size. 16S rDNA sequencing, flow cytometry (FCM), and Western blotting were also conducted to investigate the changes in the gut microbiota, tumour immune microenvironment, and apoptotic proteins, respectively. The results demonstrated that aspirin significantly exerted anti-CRC effects in mice. According to 16S rDNA sequencing, aspirin regulated the composition of the gut microbiota and dramatically reduced the abundance of Enterococcus cecorum. FCM demonstrated that there were more CD155 tumour cells and CD4 + CD25 + Treg cells showed increased TIGIT levels. Moreover, increased TIGIT expression on Treg cells is associated with reduced Treg cell functionality. Importantly, the inhibition of Treg cells is accompanied by the promotion of CD19 + GL-7 + B cells, CD8 + T cells, CD4 + CCR4 + Th2 cells, and CD4 + CCR6 + Th17 cells. Overall, aspirin prevents colorectal cancer by regulating the abundance of Enterococcus cecorum and TIGIT + Treg cells.

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Targeting Post-Translational Regulation of p53 in Colorectal Cancer by Exploiting Vulnerabilities in the p53-MDM2 Axis

Cited by 5 publications

References 117 publications

The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer

The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer

Anticancer effect of involucrasin A on colorectal cancer cells by modulating the Akt/MDM2/p53 pathway

Aspirin prevents colorectal cancer by regulating the abundance of Enterococcus cecorum and TIGIT+Treg cells

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