A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer

被引：23

作者：

Tanton, Helen ^{[1
]}

Sewastianik, Tomasz ^{[1
,2
]}

Seo, Hyuk-Soo ^{[3
,4
]}

Remillard, David ^{[5
]}

St Pierre, Roodolph ^{[5
]}

Bala, Pratyusha ^{[5
,6
,7
]}

Aitymbayev, Daulet ^{[5
,6
,7
]}

Dennis, Peter ^{[1
]}

Adler, Keith ^{[1
]}

Geffken, Ezekiel ^{[3
]}

Yeoh, Zoe ^{[3
]}

Vangos, Nicholas ^{[3
]}

Garbicz, Filip ^{[1
,2
]}

Scott, David ^{[3
]}

Sethi, Nilay ^{[5
,6
,7
,8
,9
,10
]}

Bradner, James ^{[5
]}

Dhe-Paganon, Sirano ^{[3
,4
]}

Carrasco, Ruben D. ^{[1
,11
]}

机构：

[1] Harvard Med Sch, Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA 02115 USA

[2] Inst Hematol & Transfus Med, Dept Expt Hematol, Warsaw, Poland

[3] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[4] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[5] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[6] Broad Inst MIT, Cambridge, MA USA

[7] Harvard Univ, Cambridge, MA 02138 USA

[8] Dana Farber Canc Inst, Gastrointestinal Canc Ctr, Boston, MA 02115 USA

[9] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA

[10] Harvard Med Sch, Boston, MA 02115 USA

[11] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

来源：

SCIENCE ADVANCES | 2022年 / 8卷 / 17期

关键词：

SMALL-MOLECULE INHIBITORS; MULTIPLE-MYELOMA; BETA-CATENIN; LIPID RAFTS; TARGET; CELL; PATHWAY; BCL9; SENSITIVITY; ACTIVATION;

D O I：

10.1126/sciadv.abm3108

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Dysregulated Wnt/beta-catenin signaling is implicated in the pathogenesis of many human cancers, including colorectal cancer (CRC), making it an attractive clinical target. With the aim of inhibiting oncogenic Wnt activity, we developed a high-throughput screening AlphaScreen assay to identify selective small-molecule inhibitors of the interaction between beta-catenin and its coactivator BCL9. We identified a compound that consistently bound to beta-catenin and specifically inhibited in vivo native beta-catenin/BCL9 complex formation in CRC cell lines. This compound inhibited Wnt activity, down-regulated expression of the Wnt/beta-catenin signature in gene expression studies, disrupted cholesterol homeostasis, and significantly reduced the proliferation of CRC cell lines and tumor growth in a xenograft mouse model of CRC. This study has therefore identified a specific small-molecule inhibitor of oncogenic Wnt signaling, which may have value as a probe for functional studies and has important implications for the development of novel therapies in patients with CRC.

引用

页数：17

共 83 条

[1] Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac [J].