title: Jnk signaling pathway-mediated regulation of Stat3 activation is linked to the development of doxorubicin resistance in cancer cell lines.
abstract: We sought to identify altered transcription factors (Stat, AP1, and NF-kB) or signal proteins (Erk1/2, p38, Akt, Jnk, Jak, and c-Src) in cancer cell lines whose growth was arrested by doxorubicin (DOX) treatment. Jnk1 was the only signal protein to be activated. DOX increased Stat3 phosphorylation, nuclear localization, and transcriptional activity. Jnk1 activation appeared to be required for Stat3 activity. Stat3 activity via the Jnk pathway was conserved in other cell lines originating from other organs. Transcriptional activity of Stat3 was increased in cells surviving DOX treatment suggesting that Stat3 activation contributed to the resistance to cytotoxicity. To better understand the role of Stat3 in Jnk1 activation, we investigated its effect on the viability of DOX-treated cells. Co-treatment with DOX and Jnk inhibitor negatively correlated with the viability of cancer cells and reduced Stat3 activity. Taken together, these results indicate that Stat3 activation via the Jnk pathway promotes the resistance of cancer cells to DOX.
authors.affiliation: Research Institute, National Cancer Center, 809 Madu 1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do 411-764, Republic of Korea.
authors.forename: Ju-Hwa
authors.initials: JH
authors.lastname: Kim
authors.forename: Seok Chul
authors.initials: SC
authors.lastname: Lee
authors.forename: Jungsil
authors.initials: J
authors.lastname: Ro
authors.forename: Han Sung
authors.initials: HS
authors.lastname: Kang
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
authors.forename: Sungpil
authors.initials: S
authors.lastname: Yoon
mesh_terms: D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases