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Allosteric inhibitor of ?-catenin selectively targets oncogenic Wnt signaling in colon cancer.

ABSTRACT: Abnormal regulation of ?-catenin initiates an oncogenic program that serves as a main driver of many cancers. Albeit challenging, ?-catenin is an attractive drug target due to its role in maintenance of cancer stem cells and potential to eliminate cancer relapse. We have identified C2, a novel ?-catenin inhibitor, which is a small molecule that binds to a novel allosteric site on the surface of ?-catenin. C2 selectively inhibits ?-catenin, lowers its cellular load and significantly reduces viability of ?-catenin-driven cancer cells. Through direct binding to ?-catenin, C2 renders the target inactive that eventually activates proteasome system for its removal. Here we report a novel pharmacologic approach for selective inhibition of ?-catenin via targeting a cryptic allosteric modulation site. Our findings may provide a new perspective for therapeutic targeting of ?-catenin.

SUBMITTER: Cheltsov A

PROVIDER: S-EPMC7229215 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Allosteric inhibitor of β-catenin selectively targets oncogenic Wnt signaling in colon cancer.

Cheltsov Anton A Nomura Natsuko N Yenugonda Venkata M VM Roper Jatin J Mukthavaram Rajesh R Jiang Pengfei P Her Nam-Gu NG Babic Ivan I Kesari Santosh S Nurmemmedov Elmar E

Scientific reports 20200515 1

Abnormal regulation of β-catenin initiates an oncogenic program that serves as a main driver of many cancers. Albeit challenging, β-catenin is an attractive drug target due to its role in maintenance of cancer stem cells and potential to eliminate cancer relapse. We have identified C2, a novel β-catenin inhibitor, which is a small molecule that binds to a novel allosteric site on the surface of β-catenin. C2 selectively inhibits β-catenin, lowers its cellular load and significantly reduces viabi ...[more]

PMID: 32415084

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Project description:BackgroundChemotherapeutic agents that modulate cell cycle checkpoints and/or tumor-specific pathways have shown immense promise in preclinical and clinical studies aimed at anti-cancer therapy. MASTL (Greatwall in Xenopus and Drosophila), a serine/threonine kinase controls the final G2/M checkpoint and prevents premature entry of cells into mitosis. Recent studies suggest that MASTL expression is highly upregulated in cancer and confers resistance against chemotherapy. However, the role and mechanism/s of MASTL mediated regulation of tumorigenesis remains poorly understood.MethodsWe utilized a large patient cohort and mouse models of colon cancer as well as colon cancer cells to determine the role of Mastl and associated mechanism in colon cancer.ResultsHere, we show that MASTL expression increases in colon cancer across all cancer stages compared with normal colon tissue (P < 0.001). Also, increased levels of MASTL associated with high-risk of the disease and poor prognosis. Further, the shRNA silencing of MASTL expression in colon cancer cells induced cell cycle arrest and apoptosis in vitro and inhibited xenograft-tumor growth in vivo. Mechanistic analysis revealed that MASTL expression facilitates colon cancer progression by promoting the β-catenin/Wnt signaling, the key signaling pathway implicated in colon carcinogenesis, and up-regulating anti-apoptotic proteins, Bcl-xL and Survivin. Further studies where colorectal cancer (CRC) cells were subjected to 5-fluorouracil (5FU) treatment revealed a sharp increase in MASTL expression upon chemotherapy, along with increases in Bcl-xL and Survivin expression. Most notably, inhibition of MASTL in these cells induced chemosensitivity to 5FU with downregulation of Survivin and Bcl-xL expression.ConclusionOverall, our data shed light on the heretofore-undescribed mechanistic role of MASTL in key oncogenic signaling pathway/s to regulate colon cancer progression and chemo-resistance that would tremendously help to overcome drug resistance in colon cancer treatment.

Dataset Information

Allosteric inhibitor of ?-catenin selectively targets oncogenic Wnt signaling in colon cancer.

Publications

Allosteric inhibitor of β-catenin selectively targets oncogenic Wnt signaling in colon cancer.

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