Jnk signaling pathway-mediated regulation of Stat3 activation is linked to the development of doxorubicin resistance in cancer cell lines

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,...

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Published in:Biochemical pharmacology 2010-02, Vol.79 (3), p.373-380
Main Authors: Kim, Ju-Hwa, Lee, Seok Chul, Ro, Jungsil, Kang, Han Sung, Kim, Hyung Sik, Yoon, Sungpil
Format: Article
Language:English
Subjects:
Biological and medical sciences
cancer
Cell Line, Tumor
Cells, Cultured
DOX resistance
Doxorubicin
Doxorubicin - pharmacology
Drug Resistance, Neoplasm - physiology
Humans
JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors
JNK Mitogen-Activated Protein Kinases - physiology
Jnk1
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - physiology
Medical sciences
Pharmacology. Drug treatments
Protein Kinase Inhibitors - pharmacology
SP600125
Stat3
STAT3 Transcription Factor - metabolism
Tumors
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Summary: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.
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2009.09.008