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 inflammation are responsible for the development of colorectal cancer. Inflammatory cytokines such as interleukin (IL)-8 and tumor necrotic factor (TNF)- a , which are released by epithelial and immune cells, are involved in the pathogenesis of colitis-associated cancer. Current treatments for advanced colorectal cancers focus primarily on targeting epidermal growth factor receptor (EGFR) signaling. IL-8 (a G-protein coupled receptor (GPCR) agonist), which is involved in neutrophil recruitment and activation in persistent active colitis, also promotes cleavage of theproheparin-binding epidermal growth factor—like growth factor (proHB-EGF) through a disintegrin and metalloproteinase (ADAM), so that the resulting soluble HB-EGF activates EGFR. In parallel, the carboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocates into the inner nuclear membrane, where HB-EGF-CTF binds the nuclear promyelocytic leukemia zinc finger (PLZF) protein, resulting in the nuclear export of the PLZF transcriptional repressor and thereby affecting cell proliferation. Screening for potent chemical inhibitors of the interactions between HB-EGF-CTF and PLZF identified telmisartan (and related compounds in corporating a biphenyl tetrazole moiety) as inhibitors of cell proliferation. Here we focus on the inhibitory effects of these compounds on cell proliferation, demonstrating the potential for targeting the nuclear translocation of HB-EGF-CTF in the treatment of colitis-associated cancer.