Phenylmethimazole decreases Toll-like receptor 3 and noncanonical Wnt5a expression in pancreatic cancer and melanoma together with tumor cell growth and migration.

Abstract

PURPOSE:

To evaluate whether (a) Wnt5a expression in pancreatic cancer and malignant melanoma cells might be associated with constitutive levels of Toll-like receptor 3 (TLR3) and/or TLR3 signaling; (b) phenylmethimazole (C10), a novel TLR signaling inhibitor, could decrease constitutive Wnt5a and TLR3 levels together with cell growth and migration; and (c) the efficacy of C10 as a potential inhibitor of pancreatic cancer and malignant melanoma cell growth in vivo.

EXPERIMENTAL DESIGN:

We used a variety of molecular biology techniques including but not limited to PCR, Western blotting, and ELISA to evaluate the presence of constitutively activated TLR3/Wnt5a expression and signaling. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based technology and scratch assays were used to evaluate inhibition of cell growth and migration, respectively. TLR3 regulation of cell growth was confirmed using small interfering RNA technology. Nude and severe combined immunodeficient mice were implanted with human pancreatic cancer and/or melanoma cells and the effects of C10 on tumor growth were evaluated.

RESULTS:

We show that constitutive TLR3 expression is associated with constitutive Wnt5a in human pancreatic cancer and malignant melanoma cell lines, that C10 can decrease constitutive TLR3/Wnt5a expression and signaling, suggesting that they are interrelated signal systems, and that C10 inhibits growth and migration in both of these cancer cell lines. We also report that C10 is effective at inhibiting human pancreatic cancer and malignant melanoma tumor growth in vivo in nude or severe combined immunodeficient mice and associate this with inhibition of signal transducers and activators of transcription 3 activation.

CONCLUSIONS:

C10 may have potential therapeutic applicability in pancreatic cancer and malignant melanoma.

• Authors: Anthony L Schwartz, Ramiro Malgor, Eric Dickerson, Ashani T Weeraratna, Andrzej Slominski, Jacobo Wortsman, Norikazu Harii, Aimee D Kohn, Randall T Moon, Frank L Schwartz, Douglas J Goetz, Leonard D Kohn, Kelly D McCall
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 12 Pg. 4114-22 (Jun 15 2009) ISSN: 1557-3265 [Electronic] United States
• PMID: 19470740 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Antithyroid Agents
• CXCL10 protein, human
• Chemokine CXCL10
• IL6 protein, human
• Interleukin-6
• Proto-Oncogene Proteins
• RNA, Small Interfering
• STAT3 Transcription Factor
• STAT3 protein, human
• TLR3 protein, human
• Thiones
• Toll-Like Receptor 3
• WNT5A protein, human
• Wnt Proteins
• Wnt-5a Protein
• phenyl methimazole
• Methimazole
• Interferon-beta

Topics

• Animals
• Antithyroid Agents (pharmacology)
• Cell Line, Tumor
• Chemokine CXCL10 (antagonists & inhibitors, metabolism)
• Gene Knockdown Techniques
• Humans
• Interferon-beta (antagonists & inhibitors, metabolism)
• Interleukin-6 (antagonists & inhibitors, metabolism)
• Melanoma (drug therapy, metabolism, pathology)
• Methimazole (analogs & derivatives, pharmacology)
• Mice
• Mice, Nude
• Mice, SCID
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• RNA, Small Interfering (metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects, physiology)
• Skin Neoplasms (drug therapy, metabolism, pathology)
• Thiones (pharmacology)
• Toll-Like Receptor 3 (antagonists & inhibitors, genetics, metabolism)
• Wnt Proteins (antagonists & inhibitors, metabolism)
• Wnt-5a Protein