KAP regulates ROCK2 and Cdk2 in an RNA-activated glioblastoma invasion pathway

H, Li; Jiang, Xin; Yu, Yinhua; Huang, Wei; Xing, Hongyan; Ny, Agar; Hw, Yang; Yang, Bo; Rs, Carroll; Johnson, _______

doi:10.1038/onc.2014.49

Cited by 26 publications

(22 citation statements)

References 36 publications

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“…Although migrating cells activate Rho GTPases to control myosin phosphorylation and cell motility, they also control GC activity and cGMP increase [43]. Indeed, GBM invasiveness has been shown to be strongly induced by negative regulation of ROCK2 activity [44–46]. We demonstrated that ROCK inhibition increased GBM invasiveness and increased Ser695 MYPT1 levels, similarly to what has been described for rat neuronal migration [47].…”

Section: Discussionsupporting

confidence: 81%

Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome

et al. 2017

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Expression of type 5 phosphodiesterase (PDE5), a cGMP-specific hydrolytic enzyme, is frequently altered in human cancer, but its specific role in tumorigenesis remains controversial. Herein, by analyzing a cohort of 69 patients affected by glioblastoma multiforme (GBM) who underwent chemo- and radiotherapy after surgical resection of the tumor, we found that PDE5 was strongly expressed in cancer cells in about 50% of the patients. Retrospective analysis indicated that high PDE5 expression in GBM cells significantly correlated with longer overall survival of patients. Furthermore, silencing of endogenous PDE5 by short hairpin lentiviral transduction (sh-PDE5) in the T98G GBM cell line induced activation of an invasive phenotype. Similarly, pharmacological inhibition of PDE5 activity strongly enhanced cell motility and invasiveness in T98G cells. This invasive phenotype was accompanied by increased secretion of metallo-proteinase 2 (MMP-2) and activation of protein kinase G (PKG). Moreover, PDE5 silencing markedly enhanced DNA damage repair and cell survival following irradiation. The enhanced radio-resistance of sh-PDE5 GBM cells was mediated by an increase of poly(ADP-ribosyl)ation (PARylation) of cellular proteins and could be counteracted by poly(ADP-ribose) polymerase (PARP) inhibitors. Conversely, PDE5 overexpression in PDE5-negative U87G cells significantly reduced MMP-2 secretion, inhibited their invasive potential and interfered with DNA damage repair and cell survival following irradiation. These studies identify PDE5 as a favorable prognostic marker for GBM, which negatively affects cell invasiveness and survival to ionizing radiation. Moreover, our work highlights the therapeutic potential of targeting PKG and/or PARP activity in this currently incurable subset of brain cancers.

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Section: Discussionsupporting

confidence: 81%

Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome

et al. 2017

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“…Rock2 belongs to the serine/threonine protein kinase family. The studies reported that Rock2 is closely associated with the occurrence and development of HCC [18]. Our previous research also revealed that Rock2 overexpression inhibits the ubiquitination‐mediated degradation of MMP2, thereby promoting HCC invasion and metastasis [10].…”

Section: Discussionmentioning

confidence: 91%

ROCK2 promotes HCC proliferation by CEBPD inhibition through phospho‐GSK3β/β‐catenin signaling

Zhou

Yuan

et al. 2015

FEBS Letters

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a b s t r a c tRho-associated kinase 2 (Rock2) is known to promote tumorigenesis in hepatocellular carcinoma (HCC). CCAAT/enhancer-binding protein delta (CEBPD) functions as a tumor suppressor. In this study, we found that the expression of Rock2 and CEBPD are inversely correlated. Knockdown of Rock2 increased CEBPD expression and inhibited the proliferation of HCC cells in vitro and in vivo. Mechanistically, we found that Rock2 regulates CEBPD expression through the p-GSK3b/bcatenin pathway. Taken together, we identified a novel Rock2-p-GSK3b/b-catenin-CEBPD regulatory circuitry, the dysfunction of which may contribute to the tumorigenic characteristic of HCC.

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“…Tumor volume was calculated according to the formula V (mm 3 ) = a × b 2 /2, where a is the longest diameter, and b is the shortest diameter of the tumor. The number of invading cells outside the tumor core was quantitatively analyzed according to previous reports 32, 33 .…”

Section: Methodsmentioning

confidence: 99%

Overexpression of RASD1 inhibits glioma cell migration/invasion and inactivates the AKT/mTOR signaling pathway

Gao

Jin

Liu

et al. 2017

Sci Rep

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The RAS signaling pathway is hyperactive in malignant glioma due to overexpression and/or increased activity. A previous study identified that RASD1, a member of the RAS superfamily of small G-proteins, is a significantly dysregulated gene in oligodendroglial tumors that responded to chemotherapy. However, the role and mechanism of RASD1 in the progression of human glioma remain largely unknown. In the present study, by analyzing a public genomics database, we found that high levels of RASD1 predicted good survival of astrocytoma patients. We thus established lentivirus-mediated RASD1-overexpressing glioma cells and found that overexpressing RASD1 had no significant effects on glioma cell proliferation. However, the overexpression of RASD1 inhibited glioma cell migration and invasion. In the intracranial glioma xenograft model, the overexpression of RASD1 significantly reduced the number of tumor cells invading into the surrounding tissues without affecting the tumor size. An intracellular signaling array revealed that the phosphorylation of both AKT and the S6 ribosomal protein significantly decreased with RASD1 overexpression in glioma cells. Interestingly, RASD1 protein levels were significantly higher in grade II and grade III astrocytoma tissues than in nontumorous brain tissues. These findings suggest that the upregulation of RASD1 in glioma tissues may play an inhibitory role in tumor expansion, possibly through inactivating the AKT/mTOR signaling pathway.

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KAP regulates ROCK2 and Cdk2 in an RNA-activated glioblastoma invasion pathway

Cited by 26 publications

References 36 publications

Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome

Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome

ROCK2 promotes HCC proliferation by CEBPD inhibition through phospho‐GSK3β/β‐catenin signaling

Overexpression of RASD1 inhibits glioma cell migration/invasion and inactivates the AKT/mTOR signaling pathway

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