Original Article
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Biol Chem. Aug 26, 2014; 5(3): 377-386
Published online Aug 26, 2014. doi: 10.4331/wjbc.v5.i3.377
Effects of acute doxorubicin treatment on hepatic proteome lysine acetylation status and the apoptotic environment
Amie J Dirks-Naylor, Samir A Kouzi, Joseph D Bero, Ngan TK Tran, Sendra Yang, Raean Mabolo
Amie J Dirks-Naylor, Samir A Kouzi, Joseph D Bero, Ngan TK Tran, Sendra Yang, Raean Mabolo, School of Pharmacy, Wingate University, Wingate, NC 28174, United States
Author contributions: Dirks-Naylor AJ designed the research, performed the research, analyzed the data, and wrote the manuscipt; Kouzi SA designed the research and performed the research and edited the manuscirpt; Bero JD, Tran NTK, Yang S and Mabolo R performed the research.
Correspondence to: Amie J Dirks-Naylor, PhD, Associate Professor, School of Pharmacy, Wingate University, 515 N. Main Street, Wingate, NC 28174, United States. anaylor@wingate.edu
Telephone: +1-704-2338341 Fax: +1-704-2338332
Received: February 18, 2014
Revised: April 2, 2014
Accepted: June 27, 2014
Published online: August 26, 2014
Processing time: 205 Days and 7.3 Hours
Abstract

AIM: To determine if doxorubicin (Dox) alters hepatic proteome acetylation status and if acetylation status was associated with an apoptotic environment.

METHODS: Doxorubicin (20 mg/kg; Sigma, Saint Louis, MO; n = 8) or NaCl (0.9%; n = 7) was administered as an intraperitoneal injection to male F344 rats, 6-wk of age. Once animals were treated with Dox or saline, all animals were fasted until sacrifice 24 h later.

RESULTS: Dox treatment decreased proteome lysine acetylation likely due to a decrease in histone acetyltransferase activity. Proteome deacetylation may likely not be associated with a proapoptotic environment. Dox did not increase caspase-9, -8, or -3 activation nor poly (adenosine diphosphate-ribose) polymerase-1 cleavage. Dox did stimulate caspase-12 activation, however, it likely did not play a role in apoptosis induction.

CONCLUSION: Early effects of Dox involve hepatic proteome lysine deacetylation and caspase-12 activation under these experimental conditions.

Keywords: Sirtuin 1; Sirtuin 3; Caspase; Apoptosis; Acetylation; Histone deacetylase; Histone acetyltransferase

Core tip: Doxorubicin (Dox) is an effective chemotherapeutic agent, but known to cause cardiotoxicity and hepatotoxicity. Cellular stress can alter proteome acetylation status in various experimental models, which has been associated with a proapoptotic environment. The effects of Dox on hepatic lysine acetylation status has not been studied. The study revealed five interesting findings that open the door for new areas of investigation: (1) Dox induces proteome lysine deacetylation; (2) lysine deacetylation is, at least in part, due to a decrease in histone acetyltransferase activity; (3) lysine deacetylation is likely not associated with an apoptotic environment; (4) Dox-induced hepatic injury is associated with caspase-12 activation; and (5) caspase-12 activation is not involved in apoptosis induction. These results may in the future translate to lysine acetylation homeostasis and/or caspase-12 as therapeutic targets.