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?2-AR activation promotes cleavage and nuclear translocation of Her2 and metastatic potential of cancer cells.

ABSTRACT: Prolonged hypersecretion of catecholamine induced by chronic stress may correlate with malignant progression of cancer. ?2-adrenergic receptor (?2-AR) overexpressed in certain cancer cells may translate the signals from neuroendocrine system to malignant signals by interacting with oncoproteins, such as Her2. In the present study, we demonstrate that catecholamine stimulation activates the expression and proteolytic activity of ADAM10 by modulating the expression of miR-199a-5p and SIRT1 and also confirm that catecholamine induction triggers the activities of ?-secretase, leading to shedding of Her2 extracellular domain (ECD) by ADAM10 and subsequent intramembranous cleavage of Her2 intracellular domain (ICD) by presenilin-dependent ?-secretase, nuclear translocation of Her2 ICD, and enhanced transcription of tumor metastasis-associated gene COX-2. Chronic stimulation of catecholamine strongly promotes the invasive activities of cancer cells in vitro and spontaneous tumor lung metastasis in mice. Furthermore, nuclear localization of Her2 was significantly correlated with overexpression of ?2-AR in human breast cancer tissues, indicating that catecholamine-induced ?2-AR activation plays decisive roles in tumor metastasis. Our data also reveal that an unknown mechanism by which the regulated intramembrane proteolysis (RIP) initiated by ?2-AR-mediated signaling controls a novel Her2-mediated signaling transduction.

SUBMITTER: Liu D

PROVIDER: S-EPMC7734010 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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β2-AR activation promotes cleavage and nuclear translocation of Her2 and metastatic potential of cancer cells.

Liu Dan D Zha Li L Liu Yuchen Y Zhao Xuan X Xu Xiyue X Liu Shuci S Ma Wen W Zheng Junnian J Shi Ming M

Cancer science 20201027 12

Prolonged hypersecretion of catecholamine induced by chronic stress may correlate with malignant progression of cancer. β2-adrenergic receptor (β2-AR) overexpressed in certain cancer cells may translate the signals from neuroendocrine system to malignant signals by interacting with oncoproteins, such as Her2. In the present study, we demonstrate that catecholamine stimulation activates the expression and proteolytic activity of ADAM10 by modulating the expression of miR-199a-5p and SIRT1 and als ...[more]

PMID: 33016509

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Project description:BackgroundRecent studies highlighted the increased frequency of AR-low or -negative prostate cancers (PCas) and the importance of AR-independent mechanisms in driving metastatic castration-resistant PCa (mCRPC) development and progression. Several previous studies have highlighted the involvement of the MEN1 gene in PCa. In the current study, we focused on its role specifically in AR-independent PCa cells.MethodsCell tumorigenic features were evaluated by proliferation assay, foci formation, colony formation in soft agar, wound healing assay and xenograft experiments in mice. Quantitative RT-PCR, Western blot and immunostaining were performed to determine the expression of different factors in human PCa lines. Different ChIP-qPCR-based assays were carried out to dissect the action of JunD and β-catenin.ResultsWe found that MEN1 silencing in AR-independent cell lines, DU145 and PC3, resulted in an increase in anchorage independence and cell migration, accompanied by sustained MYC expression. By searching for factors known to positively regulate MYC expression and play a relevant role in PCa development and progression, we uncovered that MEN1-KD triggered the nuclear translocation of JunD and β-catenin. ChIP and 3C analyses further demonstrated that MEN1-KD led to, on the one hand, augmented binding of JunD to the MYC 5' enhancer and increased formation of loop structure, and on the other hand, increased binding of β-catenin to the MYC promoter. Moreover, the expression of several molecular markers of EMT, including E-cadherin, BMI1, Twist1 and HIF-1α, was altered in MEN1-KD DU145 and PC3 cells. In addition, analyses using cultured cells and PC3-GFP xenografts in mice demonstrated that JunD and β-catenin are necessary for the altered tumorigenic potential triggered by MEN1 inactivation in AR-independent PCa cells. Finally, we observed a significant negative clinical correlation between MEN1 and CTNNB1 mRNA expression in primary PCa and mCRPC datasets.ConclusionsOur current work highlights an unrecognized oncosuppressive role for menin specifically in AR-independent PCa cells, through the activation of JunD and β-catenin pathways.

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?2-AR activation promotes cleavage and nuclear translocation of Her2 and metastatic potential of cancer cells.

Publications

β2-AR activation promotes cleavage and nuclear translocation of Her2 and metastatic potential of cancer cells.

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