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Role of IKK and oscillatory NFκB kinetics in MMP‐9 gene expression and chemoresistance to 5‐fluorouracil in RKO colorectal cancer cells
Author(s) -
Fukuyama Ryuichi,
Ng Kwok Peng,
Cicek Muzaffer,
Kelleher Clare,
Niculaita Roxana,
Casey Graham,
Sizemore Nywana
Publication year - 2007
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20288
Subject(s) - iκb kinase , biology , nf κb , iκbα , nfkb1 , cancer research , tumor necrosis factor alpha , cell culture , signal transduction , phosphorylation , matrix metalloproteinase , microbiology and biotechnology , medicine , endocrinology , gene , transcription factor , biochemistry , genetics
Nuclear factor kappa B (NFκB) is a central participant in the metastasis and chemoresistance of colorectal cancer (CRC). However, it is not fully understood to what extent NFκB contributes to induction of the metastasis‐associated matrix metalloprotease‐9 ( MMP‐9 ) gene and sensitivity to the commonly used chemotherapeutic 5‐fluorouracil (5‐Fu) in CRC. Using the RKO human CRC cell line and two NFκB signaling deficient RKO mutants, we investigated NFκB's role in the induction of MMP‐9 and 5‐Fu sensitivity in RKO CRC cells. NFκB plays a predominant role in MMP‐9 gene induction in RKO cells, as evidenced by the failure of tumor necrosis factor alpha (TNFα) to induce MMP‐9 in either of the NFκB signaling mutants. RKO cells exhibit a robust, oscillatory NFκB activity in response to TNFα not seen in either of the NFκB mutant cell lines, which instead demonstrate diminished, nonoscillatory NFκB activation. Analysis of TNFα‐induced phosphorylation and MMP‐9 promoter recruitment of the p65 NFκB subunit revealed a significant reduction in p65 phosphorylation as well as reduced and altered recruitment of p65 to the MMP‐9 gene promoter in the mutants compared to the parental RKO cell line. 5‐Fu only activated NFκB in the parental RKO cells through induction of IκB‐kinase (IKK) activity and increased sensitivity to 5‐Fu is observed in both NFκB mutant lines. Our results suggest that TNFα‐dependent induction of MMP‐9 gene expression is tightly regulated by oscillatory/cumulative activation of NFκB and that 5‐Fu stimulates NFκB and RKO CRC cell survival through induction of IKK activity. © 2006 Wiley‐Liss, Inc.