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TP53 和抗衰老 DDR1 受体对控制前列腺癌细胞系中 Raf/MEK/ERK 和 PI3K/Akt 表达及化疗药物敏感性的影响。

Influences of TP53 and the anti-aging DDR1 receptor in controlling Raf/MEK/ERK and PI3K/Akt expression and chemotherapeutic drug sensitivity in prostate cancer cell lines.

机构信息

Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

Current Address: Becton, Dickinson and Company (BD), BD Diagnostics, Franklin Lakes, NJ 07417, USA.

出版信息

Aging (Albany NY). 2020 Jun 3;12(11):10194-10210. doi: 10.18632/aging.103377.

DOI:10.18632/aging.103377
PMID:32492656
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7346063/
Abstract

BACKGROUND

TP53 plays critical roles in sensitivity to chemotherapy, and aging. Collagen is very important in aging. The molecular structure and biochemical properties of collagen changes during aging. The discoidin domain receptor (DDR1) is regulated in part by collagen. Elucidating the links between TP53 and DDR1 in chemosensitivity and aging could improve therapies against cancer and aging.

RESULTS

Restoration of WT-TP53 activity resulted in increased sensitivity to chemotherapeutic drugs and elevated expression of key components of the Raf/MEK/ERK, PI3K/Akt and DDR1 pathways. DDR1 could modulate the levels of Raf/MEK/ERK and PI3K/Akt pathways as well as sensitize the cells to chemotherapeutic drugs. In contrast, suppression of WT TP53 with a dominant negative (DN) TP53 gene, suppressed DDR1 protein levels and increased their chemoresistance.

CONCLUSION

Restoration of WT TP53 activity or increased expression of the anti-aging DDR1 collagen receptor can result in enhanced sensitivity to chemotherapeutic drugs. Our innovative studies indicate the important links between WT TP53 and DDR1 which can modulate Raf/MEK/ERK and PI3K/Akt signaling as well as chemosensitivity and aging.

METHODS

We investigated the roles of wild type (WT) and mutant TP53 on drug sensitivity of prostate cancer cells and the induction of Raf/MEK/ERK, PI3K/Akt and DDR1 expression and chemosensitivity.

摘要

背景

TP53 在化疗敏感性和衰老中起着关键作用。胶原蛋白在衰老中非常重要。胶原蛋白的分子结构和生化特性在衰老过程中发生变化。盘状结构域受体（DDR1）部分受胶原蛋白调节。阐明 TP53 和 DDR1 在化疗敏感性和衰老中的联系，可以改善针对癌症和衰老的治疗方法。

结果

WT-TP53 活性的恢复导致对化疗药物的敏感性增加，以及 Raf/MEK/ERK、PI3K/Akt 和 DDR1 途径的关键成分的表达升高。DDR1 可以调节 Raf/MEK/ERK 和 PI3K/Akt 途径的水平，并使细胞对化疗药物敏感。相比之下，用显性负（DN）TP53 基因抑制 WT TP53，抑制 DDR1 蛋白水平并增加其化疗耐药性。

结论

WT TP53 活性的恢复或抗衰老 DDR1 胶原蛋白受体的表达增加，可导致对化疗药物的敏感性增强。我们的创新性研究表明，WT TP53 和 DDR1 之间存在重要联系，可调节 Raf/MEK/ERK 和 PI3K/Akt 信号以及化疗敏感性和衰老。

方法

我们研究了野生型（WT）和突变型 TP53 对前列腺癌细胞药物敏感性的作用，以及 Raf/MEK/ERK、PI3K/Akt 和 DDR1 表达和化疗敏感性的诱导。

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