DNA topoisomerase I is a cofactor for c-Jun in the regulation of epidermal growth factor receptor expression and cancer cell proliferation.
DNA topoisomerase I (Topo I) is a molecular target for the anticancer agent topotecan in the treatment of small cell lung cancer and ovarian carcinomas. However, the molecular mechanisms by which topotecan treatment inhibits cancer cell proliferation are unclear. We describe here the identification of Topo I as a novel endogenous interaction partner for transcription factor c-Jun. Reciprocal coimmunoprecipitation analysis showed that Topo I and c-Jun interact in transformed human cells in a manner that is dependent on JNK activity. c-Jun target gene epidermal growth factor receptor (EGFR) was identified as a novel gene whose expression was specifically inhibited by topotecan. Moreover, Topo I overexpression supported c-Jun-mediated reporter gene activation and both genetic and chemical inhibition of c-Jun converted cells resistant to topotecan-elicited EGFR downregulation. Topotecan-elicited suppression of proliferation was rescued by exogenously expressed EGFR. Furthermore, we demonstrate the cooperation of the JNK-c-Jun pathway, Topo I, and EGFR in the positive regulation of HT-1080 cell proliferation. Together, these results have identified transcriptional coactivator Topo I as a first endogenous cofactor for c-Jun in the regulation of cell proliferation. In addition, the results of the present study strongly suggest that inhibition of EGFR expression is a novel mechanism by which topotecan inhibits cell proliferation in cancer therapy.
Mialon
Antoine
A
Centre for Biotechnology, University of Turku and Abo Akademi University, Tykistökatu 6B, 20520 Turku, Finland.
Sankinen
Matti
M
Söderström
Henrik
H
Junttila
Teemu T
TT
Holmström
Tim
T
Koivusalo
Riku
R
Papageorgiou
Anastassios C
AC
Johnson
Randall S
RS
Hietanen
Sakari
S
Elenius
Klaus
K
Westermarck
Jukka
J
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000378:metabolism / Q000627:therapeutic use; D015533:Transcriptional Activation
D000970:Antineoplastic Agents; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D004264:DNA Topoisomerases, Type I