5'-Nitro-indirubinoxime inhibits epidermal growth factor- and phorbol ester-induced AP-1 activity and cell transformation through inhibition of phosphorylation of Pin1.

Abstract

5'-Nitro-indirubinoxime (5'-NIO), a derivative of indirubin, exhibits anti-cancer activity in a variety of human cancer cells. However, the underlying molecular mechanisms and molecular target(s) of the chemopreventive activities of 5'-NIO remain unknown. Here, we report that 5'-NIO inhibited the epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic cell transformation of JB6 Cl41 mouse skin epidermal cells without any cytotoxic effects. Western blot analysis revealed that 5'-NIO inhibited activities of Raf-1 (S338), MEK1/2, ERK1/2, JNK, and c-Jun induced by EGF or TPA, respectively, whereas it did not affect autophosphorylation of epidermal growth factor receptor (EGFR) induced by EGF or TPA. In addition, 5'-NIO exerted strong inhibitory effects on the EGF- or TPA-induced c-fos or c-jun transcriptional activity, and thereby inhibited the associated activator protein-1 (AP-1) transactivation activity induced by EGF or TPA. Importantly, 5'-NIO inhibited Pin1 phosphorylation at serine 16 induced by EGF or TPA, respectively, resulted in the inhibition of interaction between Pin1 and Raf-1. Immunoprecipitation/immunoblot analysis revealed that 5'-NIO bound with Pin1. Together, these findings suggest that 5'-NIO might act as an anticarcinogene in EGF- or TPA-induced carcinogenesis through the inhibition of interaction between Pin1 and Raf-1. © 2011 Wiley Periodicals, Inc.

• Authors: Prem Khanal, Hoo-Kyun Choi, Gwang Mo Namgoong, Sang-Gun Ahn, Jung-Hoon Yoon, Honglae Sohn, Hong Seok Choi
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 50 Issue 12 Pg. 961-71 (Dec 2011) ISSN: 1098-2744 [Electronic] United States
• PMID: 21400615 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Wiley Periodicals, Inc.

Chemical References

• 5'-nitroindirubinoxime
• Anticarcinogenic Agents
• Indoles
• NIMA-Interacting Peptidylprolyl Isomerase
• Oximes
• Proto-Oncogene Proteins c-fos
• Transcription Factor AP-1
• Epidermal Growth Factor
• Proto-Oncogene Proteins c-raf
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• PIN1 protein, human
• Peptidylprolyl Isomerase
• Pin1 protein, mouse
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Anticarcinogenic Agents (pharmacology)
• Cell Line
• Cell Transformation, Neoplastic (drug effects)
• Epidermal Growth Factor (pharmacology)
• Indoles (pharmacology)
• JNK Mitogen-Activated Protein Kinases (genetics, metabolism)
• MAP Kinase Signaling System (drug effects)
• Mice
• Mitogen-Activated Protein Kinases (antagonists & inhibitors)
• NIMA-Interacting Peptidylprolyl Isomerase
• Oximes (pharmacology)
• Peptidylprolyl Isomerase (metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-fos (genetics, metabolism)
• Proto-Oncogene Proteins c-raf (antagonists & inhibitors, metabolism)
• Tetradecanoylphorbol Acetate (pharmacology)
• Transcription Factor AP-1 (antagonists & inhibitors, metabolism)
• Transcription, Genetic (drug effects)
• Transcriptional Activation (drug effects)