P38 MAP kinase functions as a switch in MS-275-induced reactive oxygen species-dependent autophagy and apoptosis in human colon cancer cells.

Abstract

MS-275 is a synthetic benzamide derivative of the histone deacetylase inhibitor and is currently in phase I/II clinical trials. Many reports have shown that the anti-tumor activity of MS-275 in several types of cancer is mainly attributable to its capacity to induce the apoptotic death of tumor cells. It remains unclear if autophagy is involved in MS-275 treatment of cancer cells. Here, we first show that MS-275 induces human colon cancer cell HCT116 autophagy as well as apoptosis. Short-term treatment (24h) induced HCT116 cells to undergo autophagy with dependence on intracellular reactive oxygen species production and ERK activation. The activated reactive oxygen species/ERK signal promoted Atg7 protein expression, which triggered MS-275-induced cancer cell autophagy. However, after prolonged treatment with MS-275 (over 48h), autophagic cells turned apoptotic, which was also dependent on reactive oxygen species generation. Interestingly, we found that p38 MAP kinase played a vital role in the switch from autophagy to apoptosis in MS-275-induced human colon cancer cells. High expression of p38 induced cell autophagy, but low expression resulted in apoptosis. In addition, observations in vivo are strongly consistent with the in vitro results. Therefore, these findings extend our understanding of the action of MS-275 in inducing cancer cell death and suggest that it may be a promising clinical chemotherapeutic agent with multiple effects.

• Authors: Yao Zhan, Ke Gong, Chao Chen, Haiqing Wang, Wenhua Li
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 53 Issue 3 Pg. 532-43 (Aug 01 2012) ISSN: 1873-4596 [Electronic] United States
• PMID: 22634147 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Benzamides
• Free Radical Scavengers
• Pyridines
• Reactive Oxygen Species
• entinostat
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases
• Atg7 protein, human
• Autophagy-Related Protein 7
• Ubiquitin-Activating Enzymes
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Autophagy-Related Protein 7
• Benzamides (administration & dosage, pharmacology)
• Cell Survival (drug effects)
• Colorectal Neoplasms (drug therapy, enzymology, pathology)
• Enzyme Activation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Free Radical Scavengers (pharmacology)
• HCT116 Cells
• Humans
• MAP Kinase Signaling System
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Phosphorylation
• Protein Processing, Post-Translational
• Pyridines (administration & dosage, pharmacology)
• Reactive Oxygen Species (metabolism)
• Tumor Burden (drug effects)
• Ubiquitin-Activating Enzymes (genetics, metabolism)
• Up-Regulation (drug effects)
• Xenograft Model Antitumor Assays
• p38 Mitogen-Activated Protein Kinases (metabolism, physiology)