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Targeting Rho GTPase effector p21 activated kinase 4 (PAK4) suppresses p-Bad-microRNA drug resistance axis leading to inhibition of pancreatic ductal adenocarcinoma proliferation.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and therapy resistant malignancy. Mutant K-Ras, found in >90% of refractory PDAC, acts as a molecular switch activating Rho GTPase signaling that in turn promotes a plethora of pro-survival molecules and oncogenic microRNAs. We investigated the impact of Rho GTPase effector protein p21 activated kinase 4 (PAK4) inhibition on pro-survival p-Bad and oncogenic miRNA signaling. We demonstrate that the dual NAMPT and PAK4 modulators (KPT-9274 and KPT-9307) inhibit PDAC cell proliferation through downregulation of Bad phosphorylation and upregulation of tumor suppressive miRNAs (miR-145, let-7c, let-7d, miR-34c, miR320 and miR-100). These results suggest that targeting PAK4 could become a promising approach to restore pro-apoptotic function of Bad and simultaneously activate tumor suppressive miRNAs in therapy resistant PDAC.

SUBMITTER: Mohammad RM

PROVIDER: S-EPMC6748371 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Targeting Rho GTPase effector p21 activated kinase 4 (PAK4) suppresses p-Bad-microRNA drug resistance axis leading to inhibition of pancreatic ductal adenocarcinoma proliferation.

Mohammad Ramzi M RM Li Yiwei Y Muqbil Irfana I Aboukameel Amro A Senapedis William W Baloglu Erkan E Landesman Yosef Y Philip Philip A PA Azmi Asfar S AS

Small GTPases 20170623 5

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and therapy resistant malignancy. Mutant K-Ras, found in >90% of refractory PDAC, acts as a molecular switch activating Rho GTPase signaling that in turn promotes a plethora of pro-survival molecules and oncogenic microRNAs. We investigated the impact of Rho GTPase effector protein p21 activated kinase 4 (PAK4) inhibition on pro-survival p-Bad and oncogenic miRNA signaling. We demonstrate that the dual NAMPT and PAK4 modulators (KPT- ...[more]

PMID: 28641032

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Project description:BackgroundRho GTPase-activating protein 11A (ARHGAP11A) is a member of the Rho GTPase-activating protein (RhoGAP) subfamily. However, its expression, prognostic significance and clinicopathologic factors correlation in lung adenocarcinoma is still unclear.MethodsThe original gene expression profile, survival data, and clinical information of patients with lung adenocarcinoma (LUAD) were downloaded from The Cancer Genome Atlas (TCGA) database. The expression difference of ARHGAP11A between LUAD tissues and adjacent normal tissues in the TCGA database was analyzed by using R software, and verified by the Oncomine database and immunohistochemical (IHC) assay of LUAD sections. Logistic regression was applied to analyze the relationship between the expression of ARHGAP11A and clinicopathological factors of LUAD. Kaplan-Meier (KM) survival curves and a Cox proportional-hazards model were selected to evaluate the prognostic significance of ARHGAP11A expression. Gene set enrichment analysis (GSEA) software was applied to screen the tumor signaling pathways associated with the low and high expression group of ARHGAP11A in LUAD.ResultsThe TCGA database showed that the expression of ARHGAP11A was significantly higher in LUAD tissues than in normal tissues (P<0.001). The up-regulation of ARHGAP11A in LUAD was verified by the Oncomine database (P<0.001) and IHC assay (P<0.001). Logistic regression analysis revealed the high expression of ARHGAP11A to be closely related to age, sex, advanced pathological stage, advanced T stage, and lymph node metastasis. The KM plots based on the TCGA and KM plotter databases indicated that patients with LUAD highly expressing ARHGAP11A had a poorer overall survival (OS) than patients with low expression of ARHGAP11A. Multivariate Cox regression analysis showed that the high expression of ARHGAP11A could be an important independent predictor of a poor prognosis of LUAD [hazards ratio (HR) =1.385; P<0.001]. GSEA indicated that 10 signal pathways were significantly enriched in LUAD samples with the ARHGAP11A expression phenotype.ConclusionsARHGAP11A may play a carcinogenic role in the malignant progression of LUAD, and it can be considered as a new independent prognostic factor and potential therapeutic target for LUAD.

Dataset Information

Targeting Rho GTPase effector p21 activated kinase 4 (PAK4) suppresses p-Bad-microRNA drug resistance axis leading to inhibition of pancreatic ductal adenocarcinoma proliferation.

Publications

Targeting Rho GTPase effector p21 activated kinase 4 (PAK4) suppresses p-Bad-microRNA drug resistance axis leading to inhibition of pancreatic ductal adenocarcinoma proliferation.

Similar Datasets

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