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HMOB3 modulates MST1 apoptotic signaling and supports tumor growth in glioblastoma multiforme.

ABSTRACT: New therapeutic targets are needed that circumvent inherent therapeutic resistance of glioblastoma multiforme (GBM). Here, we report such a candidate target in the uncharacterized adaptor protein hMOB3, which we show is upregulated in GBM. In a search for its biochemical function, we found that hMOB3 specifically interacts with MST1 kinase in response to apoptotic stimuli and cell-cell contact. Moreover, hMOB3 negatively regulated apoptotic signaling by MST1 in GBM cells by inhibiting the MST1 cleavage-based activation process. Physical interaction between hMOB3 and MST1 was essential for this process. In vivo investigations established that hMOB3 sustains GBM cell growth at high cell density and promotes tumorigenesis. Our results suggest hMOB3 as a candidate therapeutic target for the treatment of malignant gliomas.

SUBMITTER: Tang F

PROVIDER: S-EPMC4102567 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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hMOB3 modulates MST1 apoptotic signaling and supports tumor growth in glioblastoma multiforme.

Tang Fengyuan F Zhang Lei L Xue Gongda G Hynx Debby D Wang Yuhua Y Cron Peter D PD Hundsrucker Christian C Hergovich Alexander A Frank Stephan S Hemmings Brian A BA Schmitz-Rohmer Debora D

Cancer research 20140528 14

New therapeutic targets are needed that circumvent inherent therapeutic resistance of glioblastoma multiforme (GBM). Here, we report such a candidate target in the uncharacterized adaptor protein hMOB3, which we show is upregulated in GBM. In a search for its biochemical function, we found that hMOB3 specifically interacts with MST1 kinase in response to apoptotic stimuli and cell-cell contact. Moreover, hMOB3 negatively regulated apoptotic signaling by MST1 in GBM cells by inhibiting the MST1 c ...[more]

PMID: 24872389

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Project description:BACKGROUND:Lycorine has been revealed to inhibit the development of many kinds of malignant tumors, including glioblastoma multiforme (GBM). Although compelling evidences demonstrated Lycorine's inhibition on cancers through some peripheral mechanism, in-depth mechanism studies of Lycotine's anti-GBM effects still call for further exploration. Epidermal Growth Factor Receptor (EGFR) gene amplification and mutations are the most common oncogenic events in GBM. Targeting EGFR by small molecular inhibitors is a rational strategy for GBM treatment. METHODS:The molecular docking modeling and in vitro EGFR kinase activity system were employed to identify the potential inhibitory effects of Lycorine on EGFR. And the Biacore assay was used to confirm the direct binding status between Lycorine and the intracellular EGFR (696-1022) domain. In vitro assays were conducted to test the suppression of Lycorine on the biological behavior of GBM cells. By RNA interference, EGFR expression was reduced then cells underwent proliferation assay to investigate whether Lycorine's inhibition on GBM cells was EGFR-dependent or not. RT-PCR and western blotting analysis were carried out to investigate the underlined molecular mechanism that Lycorine exerted on EGFR itself and EGFR signaling pathway. Three different xenograft models (an U251-luc intracranially orthotopic transplantation model, an EGFR stably knockdown U251 subcutaneous xenograft model and a patient-derived xenograft model) were performed to verify Lycorine's therapeutic potential on GBM in vivo. RESULTS:We identified a novel small natural molecule Lycorine binding to the intracellular EGFR (696-1022) domain as an inhibitor of EGFR. Lycorine decreased GBM cell proliferation, migration and colony formation by inducing cell apoptosis in an EGFR-mediated manner. Furthermore, Lycorine inhibited the xenograft tumor growths in three animal models in vivo. Besides, Lycorine impaired the phosphorylation of EGFR, AKT, which were mechanistically associated with expression alteration of a series of cell survival and death regulators and metastasis-related MMP9 protein. CONCLUSIONS:Our findings identify Lycorine directly interacts with EGFR and inhibits EGFR activation. The most significant result is that Lycorine displays satisfactory therapeutic effect in our patient-derived GBM tumor xenograft, thus supporting the conclusion that Lycorine may be considered as a promising candidate in clinical therapy for GBM.

Dataset Information

HMOB3 modulates MST1 apoptotic signaling and supports tumor growth in glioblastoma multiforme.

Publications

hMOB3 modulates MST1 apoptotic signaling and supports tumor growth in glioblastoma multiforme.

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