2-methoxy-5-amino-N-hydroxybenzamide sensitizes colon cancer cells to TRAIL-induced apoptosis by regulating death receptor 5 and survivin expression.

Abstract

TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis is a crucial event in the control of tumor growth. However, many cancer cells, including colon cancer cells, are resistant to TRAIL-driven cell death. We have recently shown that 2-methoxy-5-amino-N-hydroxybenzamide (herein termed 2-14), a novel derivative of mesalamine, induces endoplasmic reticulum stress in colon cancer cells. Because endoplasmic reticulum stress-induced signals regulate the expression of molecules involved in TRAIL-driven apoptosis, we examined whether 2-14 makes colon cancer cells sensitive to TRAIL. Colon cancer cells were cultured with 2-14 and/or TRAIL. Death receptor (DR) 4/DR5 were analyzed by real-time PCR and flow cytometry. TRAIL pathway-associated proteins and extracellular signal-regulated kinase (ERK) were assessed by Western blotting. The in vivo capability of 2-14 to sensitize colon cancer cells to TRAIL-induced apoptosis was evaluated in a syngenic colon cancer model in which CT26-derived grafts were induced in mice. 2-14 promoted ERK-dependent induction of DR5, thereby enhancing TRAIL-mediated caspase-8 activation and apoptosis. Analysis of TRAIL-related pro- and antiapoptotic factors and functional studies revealed that survivin is involved in the protection of colon cancer cells against TRAIL-driven apoptosis. Notably, 2-14 enhanced ubiquitination and proteasome-mediated degradation of survivin. These data were confirmed in a murine model of TRAIL-resistant colon cancer in which 2-14 upregulated DR5, reduced survivin expression, and synergized with TRAIL in inhibiting tumor growth. Similarly, intraperitoneal administration of 2-14 to mice upregulated DR5 and downregulated survivin in a model of colitis-associated colon cancer. These findings indicate that 2-14 acts as a sensitizer for TRAIL-induced apoptosis and suggest that 2-14 can be useful in the therapy for TRAIL-resistant colon cancer.

• Authors: Carmine Stolfi, Roberta Caruso, Eleonora Franzè, Angelamaria Rizzo, Angela Rotondi, Ivan Monteleone, Massimo Claudio Fantini, Francesco Pallone, Giovanni Monteleone
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 10 Pg. 1969-81 (Oct 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21817114 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-methoxy-5-amino-N-hydroxybenzamide
• Aminosalicylic Acids
• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Survivin
• TNF-Related Apoptosis-Inducing Ligand
• Extracellular Signal-Regulated MAP Kinases

Topics

• Aminosalicylic Acids (administration & dosage, pharmacology)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Drug Synergism
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• HCT116 Cells
• HT29 Cells
• Humans
• Inhibitor of Apoptosis Proteins (biosynthesis, genetics)
• Mice
• Mice, Inbred BALB C
• Receptors, TNF-Related Apoptosis-Inducing Ligand (biosynthesis, genetics, metabolism)
• Survivin
• TNF-Related Apoptosis-Inducing Ligand (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays