title: 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.
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: F
authors.initials: F
authors.lastname: Wang
authors.forename: R
authors.initials: R
authors.lastname: Liu
authors.forename: S W
authors.initials: SW
authors.lastname: Lee
authors.forename: C M
authors.initials: CM
authors.lastname: Sloss
authors.forename: J
authors.initials: J
authors.lastname: Couget
authors.forename: J C
authors.initials: JC
authors.lastname: Cusack
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001426:Bacterial Proteins / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016762:Genes, fos; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; C028581:CRM197 (non-toxic variant of diphtheria toxin); D004815:Epidermal Growth Factor