Targeting β-catenin Signaling for Therapeutic Intervention in MEN1-deficient Pancreatic Neuroendocrine Tumours

Overview

Journal Nat Commun

Specialty Biology

Date 2014 Dec 18

PMID 25517963

Citations 43

Authors

Xiuli Jiang

Yanan Cao

Feng Li

Yutong Su

Yanli Li

Ying Peng

Yulong Cheng

Changxian Zhang

Weiqing Wang

Guang Ning

Affiliations

Soon will be listed here.

Abstract

Inactivating MEN1 mutations are the most common genetic defects present in sporadic and inherited pancreatic neuroendocrine tumours (PNETs). The lack of interventional therapies prompts us to explore the therapeutic approach of targeting β-catenin signalling in MEN1-mutant PNETs. Here we show the MEN1-encoded scaffold protein menin regulates phosphorylation of β-catenin. β-catenin signalling is activated in MEN1-mutant human and mouse PNETs. Conditional knockout of β-catenin suppresses the tumorigenesis and growth of Men1-deficient PNETs, and significantly prolongs the survival time in mice. Suppression of β-catenin signalling by genetic ablation or a molecular antagonist inhibits the expression of proproliferative genes in menin-null PNETs and potently improves hyperinsulinemia and hypoglycemia in mice. Blockade of β-catenin has no adverse effect on physiological function of pancreatic β-cells. Our data demonstrate that β-catenin signalling is an effective therapeutic target for MEN1-mutant PNETs. Our findings may contribute to individualized and combined medication treatment for PNETs.

Citing Articles

Menin in Cancer.

Majer A, Hua X, Katona B Genes (Basel). 2024; 15(9).

PMID: 39336822 PMC: 11431421. DOI: 10.3390/genes15091231.

MEN1 Deficiency-Driven Activation of the β-Catenin-MGMT Axis Promotes Pancreatic Neuroendocrine Tumor Growth and Confers Temozolomide Resistance.

Xu J, Lou X, Wang F, Zhang W, Xu X, Ye Z Adv Sci (Weinh). 2024; 11(35):e2308417.

PMID: 39041891 PMC: 11425246. DOI: 10.1002/advs.202308417.

Combined deletion of MEN1, ATRX and PTEN triggers development of high-grade pancreatic neuroendocrine tumors in mice.

Fuentes M, Lu X, Flores N, Hausmann S, Mazur P Sci Rep. 2024; 14(1):8510.

PMID: 38609433 PMC: 11014914. DOI: 10.1038/s41598-024-58874-2.

Improving susceptibility of neuroendocrine tumors to radionuclide therapies: personalized approaches towards complementary treatments.

Richter S, Steenblock C, Fischer A, Lemm S, Ziegler C, Bechmann N Theranostics. 2024; 14(1):17-32.

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Pseudoendocrine sarcoma: clinicopathologic, molecular, and epigenetic features of one case.

Vizcaino M, Folpe A, Huffman H, Panchal R, Nielsen G, Kipp B Virchows Arch. 2023; 483(6):899-904.

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