NAMPT Inhibitor and P73 Activator Represses P53 R175H Mutated HNSCC Cell Proliferation in a Synergistic Manner.

Ching-Feng Lien,Wei-Chen Wu,Ming-Han Wu,Si-Jie Yu,Yi-Chiang Hsu,Zhi-Yu Bai,Bi-He Cai,Chia-Chi Chen,Rui-Yu Lu

doi:10.3390/biom12030438

Ching-Feng Lien, Wei-Chen Wu + Show 7 more

Open Access

https://doi.org/10.3390/biom12030438

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Journal: Biomolecules	Publication Date: Mar 12, 2022
Citations: 7	License type: CC BY 4.0

Affiliation: I-Shou University, E-Da Hospital

Abstract

The p53 family has the following three members: p53, p63 and p73. p53 is a tumor suppressor gene that frequently exhibits mutation in head and neck cancer. Most p53 mutants are loss-of-function (LoF) mutants, but some acquire some oncogenic function, such as gain of function (GoF). It is known that the aggregation of mutant p53 can induce p53 GoF. The p73 activators RETRA and NSC59984 have an anti-cancer effect in p53 mutation cells, but we found that p73 activators were not effective in all head and neck squamous cell carcinoma (HNSCC) cell lines, with different p53 mutants. A comparison of the gene expression profiles of several regulator(s) in mutant HNSCC cells with or without aggregation of p53 revealed that nicotinamide phosphoribosyltransferase (NAMPT) is a key regulator of mutant p53 aggregation. An NAMPT inhibitor, to reduce abnormal aggregation of mutant p53, used in combination with a p73 activator, was able to effectively repress growth in HNSCC cells with p53 GoF mutants. This study, therefore, suggests a potential combination therapy approach for HNSCC with a p53 GoF mutation.

Highlights

The p53 family has the following three members: p53, p63 and p73 [1,2]. p53 is a tumor suppressor gene that frequently exhibits mutation in cancers [3]
It is known that the aggregation of mutant p53 can induce p53 gain of function (GoF) through sequestration of other tumor suppressor genes; such aggregation is an example of the third mechanism [11–13]
We evaluated whether the p53 R175H and V173L mutations were prone to aggregation or not, using the contact-dependent secondary structure propensity (CSSP) method [19], and assayed the aggregative signal in these two cell lines

Summary

Introduction

The p53 family has the following three members: p53, p63 and p73 [1,2]. p53 is a tumor suppressor gene that frequently exhibits mutation in cancers [3]. P53 is a tumor suppressor gene that frequently exhibits mutation in cancers [3]. Studies mostly focused on the loss of function (LoF) of the tumor suppressor role of wild-type p53, due to mutation, but, recently, there has been more focus on the gain of function (GoF) in mutant p53 proteins [5]. It is known that the aggregation of mutant p53 can induce p53 GoF through sequestration of other tumor suppressor genes; such aggregation is an example of the third mechanism [11–13]. The p73 activators RETRA and NSC59984 have an anti-cancer effect in p53-mutated cells [14,15]. Makes sense that these two p73 activators have no anti-cancer effect in p53 null or p53 wild-type cells [14,15]. P73 activators may have a different anti-cancer effect in non-aggregative and aggregative p53 mutants. This study may, provide a potential treatment strategy for malignant HNSCC tumors with p53 GoF mutants

Cell Culture and Drug Treatment

CCK8 Assay

Thioflavin T Staining

Immunocytochemistry

Real Time RT-PCR

Drug Interaction Analysis

Results

20. R175H flanking

Protein aggregation

NAMPT Inhibitor and p73 Activator Have Synergic Effects That Repress

Discussion and Conclusions