title: CXCR2 signaling regulates KRAS(G¹²D)-induced autocrine growth of pancreatic cancer.
abstract: Pharmacological inhibition of RAS, the master regulator of pancreatic ductal adenocarcinoma (PDAC), continues to be a challenge. Mutations in various isoforms of RAS gene, including KRAS are known to upregulate CXC chemokines; however, their precise role in KRAS-driven pancreatic cancer remains unclear. In this report, we reveal a previously unidentified tumor cell-autonomous role of KRAS(G12D)-induced CXCR2 signaling in mediating growth of neoplastic PDAC cells. Progressively increasing expression of mCXCR2 and its ligands was detected in the malignant ductal cells of Pdx1-cre;LSL-Kras(G12D) mice. Knocking-down CXCR2 in KRAS(G12D)-bearing human pancreatic duct-derived cells demonstrated a significant decrease in the in vitro and in vivo tumor cell proliferation. Furthermore, CXCR2 antagonists showed selective growth inhibition of KRAS(G12D)-bearing cells in vitro. Intriguingly, both genetic and pharmacological inhibition of CXCR2 signaling in KRAS(G12D)-bearing pancreatic ductal cells reduced the levels of KRAS protein, strongly implying the presence of a KRAS-CXCR2 feed-forward loop. Together, these data demonstrate the role of CXCR2 signaling in KRAS(G12D)-induced growth transformation and progression in PDAC.
authors.affiliation: Department of Pathology and Microbiology, 985900 Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Abhilasha
authors.initials: A
authors.lastname: Purohit
authors.affiliation: Department of Pathology and Microbiology, 985900 Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Varney
authors.affiliation: Department of Biochemistry and Molecular Biology, 985870 Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Rachagani
authors.affiliation: Eppley Institute, 985950 Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Michel M
authors.initials: MM
authors.lastname: Ouellette
authors.affiliation: Department of Pathology and Microbiology, 985900 Nebraska Medical Center, Omaha, NE, USA.|Department of Biochemistry and Molecular Biology, 985870 Nebraska Medical Center, Omaha, NE, USA.|Eppley Institute, 985950 Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
authors.affiliation: Department of Pathology and Microbiology, 985900 Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
mesh_terms: D000818:Animals; D017209:Apoptosis; D019898:Autocrine Communication; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C117307:KRAS protein, human; D023063:Receptors, Interleukin-8B; D016283:Proto-Oncogene Proteins p21(ras)
keywords: CXCR2; ERK; KRAS(G12D); PDAC; autocrine growth