Cellular molecular and proteomic profiling deciphers the SIRT1 controlled cell death pathways in esophageal adenocarcinoma cells.

Abstract

Worldwide prevalence of esophageal adenocarcinomas with high rates of mortality coupled with increased mutations in esophageal cells warrants investigation to understand deregulation of cell signaling pathways leading to cancer. To this end, the current study was undertaken to unravel the cell death signatures using the model human esophageal adenocarcinoma cell line-OE33. The strategy involved targeting the key epigenetic modulator SIRT1, a histone deacetylase by a small molecule inhibitor - sirtinol. Sirtinol induced a dose-dependent inhibition of cell viability under both normoxic and hypoxic conditions with long term impact on proliferation as shown by clonogenic assays. Signature apoptotic signaling pathways including caspase activation and decreased Bcl-2 were observed. Proteomic analysis highlighted an array of entities affected including molecules involved in replication, transcription, protein synthesis, cell division control, stress-related proteins, spliceosome components, protein processing and cell detoxification/degradation systems. Importantly, the stoichiometry of the fold changes of the affected proteins per se could govern the cell death phenotype by sirtinol. Sirtinol could also potentially curb resistant and recurrent tumors that reside in hypoxic environments. Overall, in addition to unraveling the cellular, molecular and proteomics basis of SIRT1 inhibition, the findings open up avenues for designing novel strategies against esophageal adenocarcinoma.

• Authors: Huige Jiang, Ketki Patil, Aksal Vashi, Yuyan Wang, Emily Strickland, S Balakrishna Pai
• Journal: Cancer treatment and research communications (Cancer Treat Res Commun) Vol. 26 Pg. 100271 ( 2021) ISSN: 2468-2942 [Electronic] England
• PMID: 33341453 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• BCL2 protein, human
• Benzamides
• Naphthols
• Proto-Oncogene Proteins c-bcl-2
• sirtinol
• SIRT1 protein, human
• Sirtuin 1

Topics

• Adenocarcinoma (drug therapy, genetics, pathology)
• Apoptosis (drug effects, genetics)
• Benzamides (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• Drug Screening Assays, Antitumor
• Epigenesis, Genetic (drug effects)
• Esophageal Neoplasms (drug therapy, genetics, pathology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Naphthols (pharmacology, therapeutic use)
• Proteomics
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Signal Transduction (drug effects, genetics)
• Sirtuin 1 (antagonists & inhibitors, metabolism)