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GSK3 suppression upregulates ?-catenin and c-Myc to abrogate KRas-dependent tumors.

ABSTRACT: Mutant KRas is a significant driver of human oncogenesis and confers resistance to therapy, underscoring the need to develop approaches that disable mutant KRas-driven tumors. Because targeting KRas directly has proven difficult, identifying vulnerabilities specific for mutant KRas tumors is an important alternative approach. Here we show that glycogen synthase kinase 3 (GSK3) is required for the in vitro and in vivo growth and survival of human mutant KRas-dependent tumors but is dispensable for mutant KRas-independent tumors. Further, inhibiting phosphorylation of GSK3 substrates c-Myc on T58 and ?-catenin on S33/S37/T41 and their subsequent upregulation contribute to the antitumor activity of GSK3 inhibition. Importantly, GSK3 blockade inhibits the in vivo growth of G12D, G12V, and G12C mutant KRas primary and metastatic patient-derived xenografts from pancreatic cancer patients who progressed on chemo- and radiation therapies. This discovery opens new avenues to target mutant KRas-dependent cancers.

SUBMITTER: Kazi A

PROVIDER: S-EPMC6279809 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

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GSK3 suppression upregulates β-catenin and c-Myc to abrogate KRas-dependent tumors.

Kazi Aslamuzzaman A Xiang Shengyan S Yang Hua H Delitto Daniel D Trevino José J Jiang Rays H Y RHY Ayaz Muhammad M Lawrence Harshani R HR Kennedy Perry P Sebti Saïd M SM

Nature communications 20181204 1

Mutant KRas is a significant driver of human oncogenesis and confers resistance to therapy, underscoring the need to develop approaches that disable mutant KRas-driven tumors. Because targeting KRas directly has proven difficult, identifying vulnerabilities specific for mutant KRas tumors is an important alternative approach. Here we show that glycogen synthase kinase 3 (GSK3) is required for the in vitro and in vivo growth and survival of human mutant KRas-dependent tumors but is dispensable fo ...[more]

PMID: 30514931

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Project description:BackgroundIt is essential to understand the mechanisms responsible for hepatocellular carcinoma (HCC) progression and chemoresistance in order to identify prognostic biomarkers as well as potential therapeutic avenues. Recent findings have shown that SLIT3 appears to function as a novel tumor suppressor gene in various types of cancers, yet its clinical correlation and role in HCC has not been understood clearly.MethodsWe determined the transcript levels of Slit3 in tumor and adjacent normal tissues within two cohorts (N?=?40 and 25) of HCC patients, and correlated the gene expression with the clinicopathological data. Subsequently, the functional effects and underlying molecular mechanisms of Slit3 overexpression and/or repression were studied using cell-line and mouse models.ResultsOur results demonstrated a repression in Slit3 expression in nearly 50% of the HCC patients, while the overall expression of Slit3 inversely correlated with the size of the tumor in both cohorts of patients. Stable down-regulation of Slit3 in HCC cell-lines induced cell proliferation in vitro and tumor growth in vivo, while stable Slit3 overexpression repressed these effects. Molecular investigations showed that the stable Slit3 repression-induced cell proliferation was associated with a higher expression of ?-catenin and a repressed GSK3? activity. Moreover, Slit3-repression induced chemoresistance to sorafenib, oxaliplatin and 5-FU through impairment of ?-catenin degradation and induction of cyclin D3 and survivin levels. The effects induced by stable Slit3-repression were diminished by transient repression of ?-catenin by siRNA approach.ConclusionThis study suggests that Slit3 acts as a tumor suppressor in HCC by repressing the tumor growth and thus tumor progression. Low Slit3 level indicates a poor response of HCC cells to chemotherapy. Restoration or overexpression of Slit3 is a potential therapeutic approach to repress the tumor growth and enhance the efficacy of chemotherapeutic agents.

Dataset Information

GSK3 suppression upregulates ?-catenin and c-Myc to abrogate KRas-dependent tumors.

Publications

GSK3 suppression upregulates β-catenin and c-Myc to abrogate KRas-dependent tumors.

Similar Datasets

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