Aging
Navigate
Submit an Article
Research Paper|Volume 12, Issue 11|pp 10194—10210

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

William H. Chappell1,2, Saverio Candido3,4, Stephen L. Abrams1, Shaw M. Akula1, Linda S. Steelman1, Alberto M. Martelli5, Stefano Ratti5, Lucio Cocco5, Melchiorre Cervello6, Giuseppe Montalto6,7, Ferdinando Nicoletti4, Massimo Libra3,4, James A. McCubrey1
  • 1Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
  • 2Current Address: Becton, Dickinson and Company (BD), BD Diagnostics, Franklin Lakes, NJ 07417, USA
  • 3Research Center for Prevention, Diagnosis and Treatment of Cancer (PreDiCT), University of Catania, Catania, Italy
  • 4Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
  • 5Department of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy
  • 6Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
  • 7Department of Health Promotion, Maternal and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
* Co-first authors
Received: December 12, 2019Accepted: May 20, 2020Published: June 3, 2020
https://doi.org/10.18632/aging.103377

Copyright © 2020 Chappell et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.