Linked Life Data

17001310

Source:http://linkedlifedata.com/resource/pubmed/id/17001310

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
14
pubmed:dateCreated
2007-3-29
pubmed:abstractText
We have shown that one of the principle mechanisms of chemotherapy resistance involves the activation of nuclear factor kappa-B (NF-kappaB). In an effort to identify NF-kappaB-regulated chemotherapy response genes, we performed a microarray assay and observed that heparin-binding EGF-like growth factor (HB-EGF) was significantly upregulated by SN38 (a strong inducer of NF-kappaB activity) in colon cancer cells. Further studies revealed that HB-EGF was rapidly induced following a variety of chemotherapy treatments. Using RNA interference, we demonstrated that the chemotherapy-induced HB-EGF was largely dependent on activator protein-1 (AP-1) and NF-kappaB activation. Constitutive HB-EGF expression rescued AP-1/NF-kappaB small interfering RNA (siRNA) cells from chemotherapy-induced apoptosis. Meanwhile, we found that the enzymatic shedding of HB-EGF was also regulated by chemotherapy treatment, resulting in the elevated release of soluble HB-EGF from the cellular membrane. Induction of HB-EGF expression and ectodomain shedding synergistically led to robust epidermal growth factor receptor (EGFR) phosphorylation, whereas inhibition of HB-EGF expression by use of the HB-EGF inhibitor (CRM197) or siRNA resulted in the suppression of chemotherapy-induced EGFR phosphorylation. These results suggest that the chemotherapy-induced EGFR activation is regulated by HB-EGF. Finally, we demonstrated that overexpression of HB-EGF led to apoptotic resistance to chemotherapy, whereas suppression of HB-EGF expression by siRNA resulted in a dramatic increase in cell death. In summary, our study suggests that chemotherapy-induced HB-EGF activation represents a critical mechanism of inducible chemotherapy resistance. Therefore, therapeutic intervention aimed at inhibiting HB-EGF activity may be useful in cancer prevention and treatments.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0950-9232
pubmed:author
pubmed:issnType
Print
pubmed:day
29
pubmed:volume
26
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2006-16
pubmed:dateRevised
2009-12-10
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Heparin-binding EGF-like growth factor is an early response gene to chemotherapy and contributes to chemotherapy resistance.
pubmed:affiliation
Division of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural