QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.107.044644v1 74/1/246    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Vasilevskaya, I. A. Articles by O'Dwyer, P. J. Search for Related Content PubMed PubMed Citation Articles by Vasilevskaya, I. A. Articles by O'Dwyer, P. J.

Disruption of Signaling through SEK1 and MKK7 Yields Differential Responses in Hypoxic Colon Cancer Cells Treated with Oxaliplatin

Abramson Family Cancer Center, University of Pennsylvania, Philadelphia, PA 19104

Transcriptional changes in response to hypoxia are regulated in part through mitogen-activated protein (MAP) kinase signaling to activator protein 1 (AP-1), and thus contribute to resistance of cancer cells to therapy, including platinum compounds. A key role for JNK in pro-apoptotic signaling in hypoxic cells has previously been established. Here we analyze hypoxic signaling through MAPK kinases to AP-1/c-Jun in the HT29 colon adenocarcinoma cell line, and observe activation of stress-activated pathways mediated predominantly by SEK1 and MKK7. In transient transfection assays, introduction of dominant-negative constructs for both MKK7 and SEK1 abolished hypoxia-induced AP-1 activation. Functional studies of the pathway using HT29-derived cell lines stably expressing mutant SEK1 or MKK7 showed impaired activation of Jun NH₂-terminal kinase (JNK) and AP-1 in response to hypoxia, more marked in MKK7-deficient than SEK1-deficient cells. Inhibition of SEK1 rendered hypoxic cells more sensitive to oxaliplatin in vitro, whereas the opposite effect was observed in MKK7-deficient cells. The mutant cell lines grown as mouse xenografts were treated with oxaliplatin, bevacizumab, or both. The SEK1-deficient tumors exhibited greater sensitivity to all treatments, whereas MKK7-deficient cells were resistant in vivo, consistent with in vitro observations. These data support a positive contribution of MKK7/JNK to oxaliplatin cytotoxicity and identify SEK1 as a potential target for reversal of hypoxic resistance to oxaliplatin.

Address correspondence to: Dr. Irina A. Vasilevskaya, University of Pennsylvania, 1020 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104. E-mail: vasilevs{at}mail.med.upenn.edu