z-logo
open-access-imgOpen Access
RK ‐287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model
Author(s) -
Mizutani Anna,
Yashiroda Yoko,
Muramatsu Yukiko,
Yoshida Haruka,
Chikada Tsubasa,
Tsumura Takeshi,
Okue Masayuki,
Shirai Fumiyuki,
Fukami Takehiro,
Yoshida Minoru,
Seimiya Hiroyuki
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13805
Subject(s) - axin2 , wnt signaling pathway , adenomatous polyposis coli , cancer research , colorectal cancer , cell growth , cancer , downregulation and upregulation , carcinogenesis , biology , chemistry , medicine , signal transduction , microbiology and biotechnology , gene , biochemistry , genetics
Aberrant activation of Wnt/β‐catenin signaling causes tumorigenesis and promotes the proliferation of colorectal cancer cells. Porcupine inhibitors, which block secretion of Wnt ligands, may have only limited clinical impact for the treatment of colorectal cancer, because most colorectal cancer is caused by loss‐of‐function mutations of the tumor suppressor adenomatous polyposis coli ( APC ) downstream of Wnt ligands. Tankyrase poly( ADP ‐ribosyl)ates ( PAR ylates) Axin, a negative regulator of β‐catenin. This post‐translational modification causes ubiquitin‐dependent degradation of Axin, resulting in β‐catenin accumulation. Tankyrase inhibitors downregulate β‐catenin and suppress the growth of APC ‐mutated colorectal cancer cells. Herein, we report a novel tankyrase‐specific inhibitor RK ‐287107, which inhibits tankyrase‐1 and ‐2 four‐ and eight‐fold more potently, respectively, than G007‐ LK , a tankyrase inhibitor that has been previously reported as effective in mouse xenograft models. RK ‐287107 causes Axin2 accumulation and downregulates β‐catenin, T‐cell factor/lymphoid enhancer factor reporter activity and the target gene expression in colorectal cancer cells harboring the shortly truncated APC mutations. Consistently, RK ‐287107 inhibits the growth of APC ‐mutated (β‐catenin‐dependent) colorectal cancer COLO ‐320 DM and SW 403 cells but not the APC ‐wild (β‐catenin‐independent) colorectal cancer RKO cells. Intraperitoneal or oral administration of RK ‐287107 suppresses COLO ‐320 DM tumor growth in NOD ‐ SCID mice. Rates of tumor growth inhibition showed good correlation with the behavior of pharmacodynamic biomarkers, such as Axin2 accumulation and MYC downregulation. These observations indicate that RK ‐287107 exerts a proof‐of‐concept antitumor effect, and thus may have potential for tankyrase‐directed molecular cancer therapy.

The content you want is available to Zendy users.

Already have an account? Click here to sign in.
Having issues? You can contact us here