School of Medicine, I-Shou University, Kaohsiung 82445, Taiwan.
Department of Medical Laboratory Science, I-Shou University, Kaohsiung 82445, Taiwan.
Biomolecules. 2022 Mar 12;12(3):438. doi: 10.3390/biom12030438.
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.
p53 家族有以下三个成员：p53、p63 和 p73。p53 是一种肿瘤抑制基因，在头颈部癌症中经常发生突变。大多数 p53 突变体是失活（Loss-of-Function，LoF）突变体，但有些获得了一些致癌功能，如获得功能（Gain-of-Function，GoF）。已知突变型 p53 的聚集可诱导 p53 GoF。p73 激活剂 RETRA 和 NSC59984 在 p53 突变细胞中具有抗癌作用，但我们发现 p73 激活剂在所有头颈部鳞状细胞癌（HNSCC）细胞系中并不都有效，存在不同的 p53 突变体。比较具有或不具有 p53 聚集的突变型 HNSCC 细胞中几种调节剂的基因表达谱，发现烟酰胺磷酸核糖转移酶（NAMPT）是突变型 p53 聚集的关键调节剂。一种 NAMPT 抑制剂，用于减少突变型 p53 的异常聚集，与 p73 激活剂联合使用，能够有效地抑制具有 p53 GoF 突变的 HNSCC 细胞的生长。因此，这项研究为具有 p53 GoF 突变的 HNSCC 提供了一种潜在的联合治疗方法。
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