Heparin-binding EGF-like growth factor is an early response gene to chemotherapy and contributes to chemotherapy resistance.

Abstract:

: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.

journal_name

Oncogene

journal_title

Oncogene

authors

Wang F,Liu R,Lee SW,Sloss CM,Couget J,Cusack JC

doi

10.1038/sj.onc.1209999

subject

Has Abstract

pub_date

2007-03-29 00:00:00

pages

2006-16

issue

14

eissn

0950-9232

issn

1476-5594

pii

1209999

journal_volume

26

pub_type

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