title: Inhibition of group 1 p21-activated kinases suppresses pancreatic stellate cell activation and increases survival of mice with pancreatic cancer.
abstract: Pancreatic cancer remains one of the most lethal of all solid tumors. Pancreatic stellate cells (PSCs) are primarily responsible for the fibrosis that constitutes the stroma and p21-activated kinase 1 (PAK1) may have a role in signalling pathways involving PSCs. This study aimed to examine the role of PAK1 in PSCs and in the interaction of PSCs with pancreatic cancer cells. Human PSCs were isolated using the modified outgrowth method. The effect of inhibiting PAK1 with group 1 PAK inhibitor, FRAX597, on cell proliferation and apoptosis in vitro was measured by thymidine incorporation and annexin V assays, respectively. The effect of depleting host PAK1 on the survival of mice with pancreatic Pan02 cell tumors was evaluated using PAK1 knockout (KO) mice. PAK1 was expressed in isolated PSCs. FRAX597 reduced the activation of PSCs, inhibited PSC proliferation, and increased PSC apoptosis at least in partial by inhibiting PAK1 activity. The decreased expression and activity of PAK1 in PAK1 KO mice tumors was associated with an increased mouse survival. These results implicate PAK1 as a regulator of PSC activation, proliferation and apoptosis. Targeting stromal PAK1 could increase therapeutic response and survival of patients with pancreatic cancer.
authors.affiliation: Department of Surgery, University of Melbourne. Austin Health, Melbourne, VIC, Australia.
authors.forename: Dannel
authors.initials: D
authors.lastname: Yeo
authors.affiliation: Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Phoebe
authors.initials: P
authors.lastname: Phillips
authors.affiliation: Department of Surgery, University of Melbourne. Austin Health, Melbourne, VIC, Australia.
authors.forename: Graham S
authors.initials: GS
authors.lastname: Baldwin
authors.affiliation: Department of Surgery, University of Melbourne. Austin Health, Melbourne, VIC, Australia.
authors.forename: Hong
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Surgery, University of Melbourne. Austin Health, Melbourne, VIC, Australia.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Nikfarjam
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D011728:Pyridones / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D054462:p21-Activated Kinases / Q000235:genetics*
chemical_list: C584676:FRAX597; D011728:Pyridones; D011743:Pyrimidines; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases
keywords: fibrosis; hypoxia; pancreatic ductal adenocarcinoma; stroma; stroma-tumor interaction