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

Ramzi M Mohammad; Yiwei Li; Irfana Muqbil; Amro Aboukameel; William Senapedis; Erkan Baloglu; Yosef Landesman; Philip A Philip; Asfar S Azmi

doi:10.1080/21541248.2017.1329694

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

Small GTPases. 2019 Sep;10(5):367-377. doi: 10.1080/21541248.2017.1329694. Epub 2017 Jun 23.

Authors

Ramzi M Mohammad¹, Yiwei Li¹, Irfana Muqbil¹, Amro Aboukameel¹, William Senapedis², Erkan Baloglu², Yosef Landesman², Philip A Philip¹, Asfar S Azmi¹

Affiliations

¹ a Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit , MI , USA.
² b Karyopharm Therapeutic Inc ., Newton , MA , USA.

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.

Keywords: K-Ras; MAPK; PAK; bad; microRNA.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Acrylamides / pharmacology
Aminopyridines / pharmacology
Carcinoma, Pancreatic Ductal / genetics
Carcinoma, Pancreatic Ductal / metabolism*
Carcinoma, Pancreatic Ductal / pathology
Cell Line, Tumor
Cell Proliferation*
Cytokines / antagonists & inhibitors
Cytokines / genetics
Cytokines / metabolism
Drug Resistance, Neoplasm*
Enzyme Activation / drug effects
Enzyme Activation / genetics
Humans
MicroRNAs / genetics
MicroRNAs / metabolism*
Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors
Nicotinamide Phosphoribosyltransferase / genetics
Nicotinamide Phosphoribosyltransferase / metabolism
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism*
Pancreatic Neoplasms / pathology
RNA, Neoplasm / genetics
RNA, Neoplasm / metabolism*
bcl-Associated Death Protein / genetics
bcl-Associated Death Protein / metabolism*
p21-Activated Kinases / genetics
p21-Activated Kinases / metabolism*

Substances

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

Grants and funding

R21 CA188818/CA/NCI NIH HHS/United States