Potential of new anti-cancer agents targeting the nuclear translocation signaling of HB-EGF C-terminal fragments during the development of colitis-associated cancer

Abstract

In inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease (CD), the duration and severity of\rinflammation are responsible for the development of colorectal cancer. Inflammatory\rcytokines such as interleukin (IL)-8 and tumor necrotic factor (TNF)-a,\rwhich are released by epithelial and immune cells, are involved in the\rpathogenesis of colitis-associated cancer. Current treatments for advanced\rcolorectal cancers focus primarily on targeting epidermal growth factor\rreceptor (EGFR) signaling. IL-8 (a G-protein coupled receptor (GPCR) agonist),\rwhich is involved in neutrophil recruitment and activation in persistent active\rcolitis, also promotes cleavage of theproheparin-binding epidermal growth\rfactor—like growth factor (proHB-EGF) through a disintegrin and metalloproteinase\r(ADAM), so that the resulting soluble HB-EGF activates EGFR. In parallel, the\rcarboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocates into the inner\rnuclear membrane, where HB-EGF-CTF binds the nuclear promyelocytic leukemia\rzinc finger (PLZF) protein, resulting in the nuclear export of the PLZF\rtranscriptional repressor and thereby affecting cell proliferation. Screening\rfor potent chemical inhibitors of the interactions between HB-EGF-CTF and PLZF\ridentified telmisartan (and related compounds in corporating a biphenyl\rtetrazole moiety) as inhibitors of cell proliferation. Here we focus on the\rinhibitory effects of these compounds on cell proliferation, demonstrating\rthe potential for targeting the nuclear translocation of HB-EGF-CTF in the\rtreatment of colitis-associated cancer.