Acrolein induces ribotoxic stress in human cancer cells regardless of p53 status.

Abstract

Acrolein (Acr) cytotoxicity contributes to chemotherapeutic activity of cyclophosphamide via metabolism of the anticancer drug. Our previous studies have shown that Acr causes ribosomal DNA (rDNA) damages, thus shuts down ribosomal RNA (rRNA) synthesis and leads to ribosomal stress in human cancer cells. Ribosome senses stress in 28S rRNA and induces subsequent activation of mitogen-activated protein kinase (MAPK) pathway which triggers ribotoxic stress response (RSR). Here, we report that cells harboring p53 or not responds differently to Acr-induced RSR. Our results show that Acr induced rRNA cleavage via the activated caspases in cancer cells with wild type p53, but not in cells with deficient p53. Furthermore, MAPK pathways were activated by Acr in cancer cells regardless of p53 status. Acr induced apoptosis in cells with wild type p53, while it induced G2/M cell cycle arrest in cancer cells with deficient p53. In conclusion, the presence of functional p53 plays a significant role in the mechanisms of Acr-induced rRNA cleavage and cell fates. Our results enhance our understanding of the molecular mechanisms of Acr-mediated antitumor activity which helps develop better therapeutic strategies for killing cancer cells with different p53 status.

• Authors: Chun-Hao Huang, Yen-Ting Chen, Jing-Heng Lin, Hsiang-Tsui Wang
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 52 Pg. 265-271 (Oct 2018) ISSN: 1879-3177 [Electronic] England
• PMID: 29964147 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• RNA, Ribosomal, 18S
• RNA, Ribosomal, 28S
• Tumor Suppressor Protein p53
• Acrolein
• Mitogen-Activated Protein Kinases

Topics

• Acrolein (toxicity)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Colonic Neoplasms (genetics)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Mitogen-Activated Protein Kinases (metabolism)
• RNA Interference
• RNA, Ribosomal, 18S (metabolism)
• RNA, Ribosomal, 28S (metabolism)
• Tumor Suppressor Protein p53 (genetics)