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.

Original languageEnglish (US)
Pages (from-to)7280-7296
Number of pages17
JournalOncotarget
Volume7
Issue number6
DOIs
StatePublished - Jan 1 2016

Fingerprint

Pancreatic Neoplasms
Growth
Adenocarcinoma
Pharmacology
CXC Chemokines
Pancreatic Ducts
Neoplasms
Protein Isoforms
Up-Regulation
Cell Proliferation
Ligands
Mutation
Genes
Proteins

Keywords

  • Autocrine growth
  • CXCR2
  • ERK
  • KRAS
  • PDAC

ASJC Scopus subject areas

  • Oncology

Cite this

CXCR2 signaling regulates KRAS(G12D)-induced autocrine growth of pancreatic cancer. / Purohit, Abhilasha; Varney, Michelle; Rachagani, Satyanarayana; Ouellette, Michel M; Batra, Surinder Kumar; Singh, Rakesh K.

In: Oncotarget, Vol. 7, No. 6, 01.01.2016, p. 7280-7296.

Research output: Contribution to journalArticle

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