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.
Authors	Ramzi M Mohammad, Yiwei Li, Irfana Muqbil, Amro Aboukameel, William Senapedis, Erkan Baloglu, Yosef Landesman, Philip A Philip, Asfar S Azmi
Journal	Small GTPases (Small GTPases) Vol. 10 Issue 5 Pg. 367-377 (09 2019) ISSN: 2154-1256 [Electronic] United States
PMID	28641032 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Video-Audio Media)
Chemical References	Acrylamides Aminopyridines BAD protein, human Cytokines KPT-9274 MicroRNAs RNA, Neoplasm bcl-Associated Death Protein Nicotinamide Phosphoribosyltransferase nicotinamide phosphoribosyltransferase, human PAK4 protein, human p21-Activated Kinases
Topics	Acrylamides (pharmacology) Aminopyridines (pharmacology) Carcinoma, Pancreatic Ductal (genetics, metabolism, pathology) Cell Line, Tumor Cell Proliferation Cytokines (antagonists & inhibitors, genetics, metabolism) Drug Resistance, Neoplasm Enzyme Activation (drug effects, genetics) Humans MicroRNAs (genetics, metabolism) Nicotinamide Phosphoribosyltransferase (antagonists & inhibitors, genetics, metabolism) Pancreatic Neoplasms (genetics, metabolism, pathology) RNA, Neoplasm (genetics, metabolism) bcl-Associated Death Protein (genetics, metabolism) p21-Activated Kinases (genetics, metabolism) Pancreatic Neoplasms

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