TITLE:
Potential of new anti-cancer agents targeting the nuclear translocation signaling of HB-EGF C-terminal fragments during the development of colitis-associated cancer
AUTHORS:
Satoshi Tanida, Keiji Ozeki, Tsutomu Mizoshita, Hironobu Tsukamoto, Hiromi Kataoka, Takashi Joh
KEYWORDS:
Inflammatory Bowel Disease; Ulcerative Colitis; Colitis-Associated Cancer; IL-8; HB-EGF-CTF; PLZF; Telmisaratan
JOURNAL NAME:
Advances in Bioscience and Biotechnology,
Vol.4 No.8B,
August
8,
2013
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.