A functional interplay between Δ133p53 and ΔNp63 in promoting glycolytic metabolism to fuel cancer cell proliferation

Gong, Lu; Pan, Xiao; Lim, Chuan-Bian; Polo, Anna de; Little, John B.; Yuan, Zhi-Min

doi:10.1038/s41388-017-0117-8

Cited by 17 publications

(18 citation statements)

References 35 publications

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“… 36 The role of ΔNp63α in regulating cancer cell metabolism has been observed in various cancers. 37 38 ΔNp63α is one of the most important markers to distinguish the two main subtypes of NSCLC, adenocarcinoma and squamous cell carcinoma. However, interestingly, the current evidence indicates that high expression of ΔNp63α could be frequently detected in lung squamous cell carcinoma, but rare in lung adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference

Kuo

Huang

Yang

et al. 2020

Molecular Therapy - Oncolytics

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Targeting metabolic reprogramming is an emerging strategy in cancer therapy. However, clinical attempts to target metabolic reprogramming have been proved to be challenging, with metabolic heterogeneity of cancer being one of many reasons that causes treatment failure. Here, we stratified non-small cell lung cancer (NSCLC) cells, mainly lung adenocarcinoma, based on their metabolic phenotypes and demonstrated that the aerobic glycolysis-preference NSCLC cell subtype was resistant to the OXPHOS-targeting inhibitors. We identified that monocarboxylate transporter 4 (MCT4), a lactate transporter, was highly expressed in the aerobic glycolysis-preference subtype with function supporting the proliferation of these cells. Glucose could induce the expression of MCT4 in these cells through a DNp63a and Sp1-dependent pathway. Next, we showed that knockdown of MCT4 increased intracellular lactate concentration and induced a reactive oxygen species (ROS)-dependent cellular apoptosis in the aerobic glycolysispreference NSCLC cell subtype. By scanning a panel of monoclonal antibodies with MCT4 neutralizing activity, we further identified a MCT4 immunoglobulin M (IgM) monoclonal antibody showing capable anti-proliferation efficacy on the aerobic glycolysis-preference NSCLC cell subtype. Our findings indicate that the metabolic heterogeneity is a critical factor for NSCLC therapy and manipulating the expression or function of MCT4 can be an effective strategy in targeting the aerobic glycolysis-preference NSCLC cell subtype.

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Section: Discussionmentioning

confidence: 99%

Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference

Kuo

Huang

Yang

et al. 2020

Molecular Therapy - Oncolytics

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“…However, in the ER+ m TP53 tumours, mp53 blocks TAp63 activity freeing up Δ133p53 to drive transcription (Figure 7D ). This raises the paradox of how Δ133p53 can transactivate genes when it would also harbour mutations, and it is known that DNA binding domain mutants of Δ133p53 are defective for transactivation [ 29 ]. A possible explanation is that as the mutations in this tumour set are all heterozygous, there is one wild type Δ133TP53 in each tumour encoding a functional, transactivation competent Δ133p53 protein.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the interferon-gamma (IFN-γ) pathway by p63 and Δ133p53 isoform in different breast cancer subtypes

Mehta

Morten²,

Antony

et al. 2018

Oncotarget

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The TP53 family consists of three sets of transcription factor genes, TP53, TP63 and TP73, each of which expresses multiple RNA variants and protein isoforms. Of these, TP53 is mutated in 25-30% of breast cancers. How TP53 mutations affect the interaction of TP53 family members and their isoforms in breast cancer is unknown. To investigate this, 3 independent breast cancer cohorts were stratified into 4 groups based on oestrogen receptor (ER) and TP53 mutation status. Using bioinformatic methodologies, principal signalling pathways associated with the expression of TP53 family members were identified. Results show an enrichment of IFN-γ signalling associated with TP63 RNA in wild type TP53 (wtTP53), ER negative (ER-) tumours and with Δ133TP53 RNA in mutant TP53 (mTP53) ER positive (ER+) tumours. Moreover, tumours with low IFN-γ signalling were associated with significantly poorer patient outcome. The predicted changes in expression of a subset of RNAs involved in IFN-γ signalling were confirmed in vitro. Our data show that different members of the TP53 family can drive transcription of genes involved in IFN-γ signalling in different breast cancer subgroups.

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“…Some of the mouse models that were generated of N-terminally truncated p53 display a similar phenotype to mutant p53 (R172H or R270H) in promoting invasion and metastasis [52]. As ∆133p53 can interact and potentiate ∆Np63 function, perhaps the interaction between mutant p53 and ∆Np63 and ∆Np73 variants as well as expression of all p53 family isoforms should be more thoroughly investigated in these models [53]. Notably, mutant p53 R175H can readily interact with both p63 and p73 ∆N isoforms [46,49].…”

Section: The Interactions Between Mutant P53 and P63 Or P73mentioning

confidence: 99%

The Diverse Functions of Mutant 53, Its Family Members and Isoforms in Cancer

Hall

Müller

2019

IJMS

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The p53 family of proteins has grown substantially over the last 40 years. It started with p53, then p63, p73, isoforms and mutants of these proteins. The function of p53 as a tumour suppressor has been thoroughly investigated, but the functions of all isoforms and mutants and the interplay between them are still poorly understood. Mutant p53 proteins lose p53 function, display dominant-negative (DN) activity and display gain-of-function (GOF) to varying degrees. GOF was originally attributed to mutant p53′s inhibitory function over the p53 family members p63 and p73. It has become apparent that this is not the only way in which mutant p53 operates as a large number of transcription factors that are not related to p53 are activated on mutant p53 binding. This raises the question to what extent mutant p53 binding to p63 and p73 plays a role in mutant p53 GOF. In this review, we discuss the literature around the interaction between mutant p53 and family members, including other binding partners, the functional consequences and potential therapeutics.

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A functional interplay between Δ133p53 and ΔNp63 in promoting glycolytic metabolism to fuel cancer cell proliferation

Cited by 17 publications

References 35 publications

Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference

Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference

Regulation of the interferon-gamma (IFN-γ) pathway by p63 and Δ133p53 isoform in different breast cancer subtypes

The Diverse Functions of Mutant 53, Its Family Members and Isoforms in Cancer

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