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5′‐Nitro‐indirubinoxime inhibits epidermal growth factor‐ and phorbol ester‐induced AP‐1 activity and cell transformation through inhibition of phosphorylation of Pin1
Author(s) -
Khanal Prem,
Choi HooKyun,
Namgoong Gwang Mo,
Ahn SangGun,
Yoon JungHoon,
Sohn Honglae,
Choi Hong Seok
Publication year - 2011
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20761
Subject(s) - 12 o tetradecanoylphorbol 13 acetate , biology , transactivation , epidermal growth factor , autophosphorylation , phosphorylation , microbiology and biotechnology , epidermal growth factor receptor , activator (genetics) , immunoprecipitation , pin1 , cancer research , biochemistry , protein kinase c , receptor , protein kinase a , transcription factor , gene , phorbol ester , isomerase
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.