title: p-21 activated kinase 4 (PAK4) maintains stem cell-like phenotypes in pancreatic cancer cells through activation of STAT3 signaling.
abstract: Pancreatic cancer (PC) remains a highly lethal malignancy due to its unusual chemoresistance and high aggressiveness. A subpopulation of pancreatic tumor cells, known as cancer stem cells (CSCs), is considered responsible not only for tumor-maintenance, but also for its widespread metastasis and therapeutic failure. Here we investigated the role of p-21 activated kinase 4 (PAK4) in driving PC stemness properties. Our data demonstrate that triple-positive (CD24(+)/CD44(+)/EpCAM(+)) subpopulation of pancreatic CSCs exhibits greater level of PAK4 as compared to triple-negative (CD24(-)/CD44(-)/EpCAM(-)) cells. Moreover, PAK4 silencing in PC cells leads to diminished fraction of CD24, CD44, and EpCAM positive cells. Furthermore, we show that PAK4-silenced PC cells exhibit decreased sphere-forming ability and increased chemosensitivity to gemcitabine toxicity. PAK4 expression is also associated with enhanced levels of stemness-associated transcription factors (Oct4/Nanog/Sox2 and KLF4). Furthermore, our data show decreased nuclear accumulation and transcriptional activity of STAT3 in PAK4-silenced PC cells and restitution of its activity leads to restoration of stem cell phenotypes. Together, our findings deliver first experimental evidence for the involvement of PAK4 in PC stemness and support its clinical utility as a novel therapeutic target in PC.
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Tyagi
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA.
authors.forename: Saravanakumar
authors.initials: S
authors.lastname: Marimuthu
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Bhardwaj
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA.
authors.forename: Sachin K
authors.initials: SK
authors.lastname: Deshmukh
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA.
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Srivastava
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama 36688, USA.
authors.forename: Ajay P
authors.initials: AP
authors.lastname: Singh
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: McClellan
authors.affiliation: Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama 36688, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Carter
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama 36688, USA. Electronic address: seemasingh@health.southalabama.edu.
authors.forename: Seema
authors.initials: S
authors.lastname: Singh
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000951:Antigens, Neoplasm / Q000032:analysis; D051927:CD24 Antigen / Q000032:analysis; D015815:Cell Adhesion Molecules / Q000032:analysis; D045744:Cell Line, Tumor; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D007527:Isoenzymes / Q000502:physiology; D000090062:Kruppel-Like Factor 4; D014411:Neoplastic Stem Cells / Q000737:chemistry*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010641:Phenotype; D050697:Retinal Dehydrogenase / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D054462:p21-Activated Kinases / Q000502:physiology*
chemical_list: D000951:Antigens, Neoplasm; D051927:CD24 Antigen; C497889:CD24 protein, human; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D018960:Hyaluronan Receptors; D007527:Isoenzymes; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; C116367:PAK4 protein, human; D054462:p21-Activated Kinases
keywords: Chemoresistance; PAK4; Pancreatic cancer; STAT3; Sphere formation; Stemness