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Tpl2 Is a Key Mediator of Arsenite-Induced Signal Transduction

¹ The Hormel Institute, University of Minnesota, Austin, Minnesota and ² Major in Biomodulation, Department of Agricultural Biotechnology, Seoul National University; ³ Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, Republic of Korea

Requests for reprints: Hyong Joo Lee, Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea. Phone: 82-2-880-4853; Fax: 82-2-873-5095; E-mail: leehyjo{at}snu.ac.kr and Zigang Dong, The Hormel Institute, University of Minnesota, 801 16th Avenue Northeast, Austin, MN 55912. Phone: 507-437-9600; Fax: 507-437-9606; E-mail: zgdong{at}hi.umn.edu.

Key Words: tumor progression locus 2 (Tpl2) • arsenite • cyclooxygenase-2 (COX-2) • prostaglandin E₂ (PGE₂)

Arsenite is a well-known human carcinogen that especially targets skin. The tumor progression locus 2 (Tpl2) gene encodes a serine/threonine protein kinase that is overexpressed in various cancer cells. However, the relevance of Tpl2 in arsenite-induced carcinogenesis and the underlying mechanisms remain to be explored. We show that arsenite increased Tpl2 kinase activity and its phosphorylation in mouse epidermal JB6 P+ cells in a dose- and time-dependent manner. Exposure to arsenite resulted in a marked induction of cyclooxygenase-2 (COX-2) and prostaglandin E₂ (PGE₂), important mediators of inflammation and tumor promotion. Treatment with a Tpl2 kinase inhibitor or Tpl2 short hairpin RNA suppressed COX-2 expression and PGE₂ production induced by arsenite treatment, suggesting that Tpl2 is critical in arsenite-induced carcinogenesis. We also found that arsenite-induced phosphorylation of extracellular signal-regulated kinases (ERK) or c-Jun NH₂-terminal kinases (JNK) was markedly suppressed by Tpl2 kinase inhibitor or Tpl2 short hairpin RNA. Inhibition of arsenite-induced ERK or JNK signaling using a pharmacologic inhibitor of ERK or JNK substantially blocked COX-2 expression. Furthermore, inhibition of Tpl2 reduced the arsenite-induced promoter activity of NF-B and activator protein-1 (AP-1), indicating that NF-B and AP-1 are downstream transducers of arsenite-triggered Tpl2. Our results show that Tpl2 plays a key role in arsenite-induced COX-2 expression and PGE₂ production and further elucidate the role of Tpl2 in arsenite signals that activate ERK/JNK and NF-B/AP-1 in JB6 P+ cells. [Cancer Res 2009;69(20):8043–9]