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PMID: 26771140 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

CXCR2 signaling regulates KRAS(G¹²D)-induced autocrine growth of pancreatic cancer.

Oncotarget ·Vol. 7 ·No. 6 ·2016-02-09 ·Pages 7280-96

Purohit A, Varney M, Rachagani S, Ouellette MM, Batra SK, Singh RK

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.

Keywords
CXCR2 ERK KRAS(G12D) PDAC autocrine growth
MeSH Terms
Animals Apoptosis Autocrine Communication Blotting, Western Carcinoma, Pancreatic Ductal/genetics,metabolism,pathology Cell Movement Cell Proliferation Female Humans Mice Mice, Nude Mutation/genetics Pancreatic Neoplasms/genetics,metabolism,pathology Proto-Oncogene Proteins p21(ras)/genetics Receptors, Interleukin-8B/metabolism Tumor Cells, Cultured Xenograft Model Antitumor Assays
Chemicals
KRAS protein, human Receptors, Interleukin-8B Proto-Oncogene Proteins p21(ras)
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Purohit Abhilasha
Department of Pathology and Microbiology, 985900 Nebraska Medical Center, Omaha, NE, USA.
Varney Michelle
Department of Pathology and Microbiology, 985900 Nebraska Medical Center, Omaha, NE, USA.
Rachagani Satyanarayana
Department of Biochemistry and Molecular Biology, 985870 Nebraska Medical Center, Omaha, NE, USA.
Ouellette Michel M
Eppley Institute, 985950 Nebraska Medical Center, Omaha, NE, USA.
Batra Surinder K
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.
Singh Rakesh K
Department of Pathology and Microbiology, 985900 Nebraska Medical Center, Omaha, NE, USA.
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Article Info
Journal
Oncotarget
Abbr.
Oncotarget
ISSN
1949-2553
DOI
10.18632/oncotarget.6906
Published
2016-02-09
Pages
7280-96
Language
English
Region
United States
NLM ID
101532965
PMCID
PMC4872785
Subset
IM
Grants
NCI NIH HHS · P30 CA036727 · United States
NCI NIH HHS · U54 CA163120 · United States
NCI NIH HHS · P30CA036727 · United States
NCI NIH HHS · U54CA163120 · United States
External Links
PubMed source DOI: 10.18632/oncotarget.6906 PMC Full Text View journal details
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