Role of Rac1-dependent NADPH oxidase in the growth of pancreatic cancer

J Du; J Liu; B J Smith; M S Tsao; J J Cullen

doi:10.1038/cgt.2010.64

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Role of Rac1-dependent NADPH oxidase in the growth of pancreatic cancer

Journal article

Open access

Peer reviewed

Role of Rac1-dependent NADPH oxidase in the growth of pancreatic cancer

J Du, J Liu, B J Smith, M S Tsao and J J Cullen

Cancer gene therapy, Vol.18(2), pp.135-143

02/2011

DOI: 10.1038/cgt.2010.64

PMCID: PMC3058504

PMID: 21037555

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Abstract

K-ras mutations occur in as high as 95% of patients with pancreatic cancer. K-ras activates Rac1-dependent NADPH oxidase, a key source of superoxide. Superoxide has an important function in pancreatic cancer cell proliferation, and scavenging or decreasing the levels of superoxide inhibits pancreatic cancer cell growth both in vitro and in vivo. DNA microarray analysis and RT-PCR has demonstrated that Rac1 is also upregulated in pancreatic cancer. The aim of this study was to determine whether inhibiting Rac1 would alter pancreatic tumor cell behavior. Human pancreatic cancer cells with mutant K-ras (MIA PaCa-2), wild-type K-ras (BxPC-3) and the immortal H6c7 cell line (pancreatic ductal epithelium) expressing K-ras oncogene (H6c7eR-KrasT) that is tumorigenic, were infected with a dominant/negative Rac1 construct (AdN17Rac1). In cells with mutant K-ras, AdN17Rac1 decreased rac activity, decreased superoxide levels and inhibited in vitro growth. However, in the BxPC-3 cell line, AdN17Rac1 did not change rac activity, superoxide levels or in vitro cell growth. Additionally, AdN17Rac1 decreased superoxide levels and inhibited in vitro growth in the KrasT tumorigenic cell line, but had no effect in the immortalized H6c7 cell line. In human pancreatic tumor xenografts, intratumoral injections of AdN17Rac1 inhibited tumor growth. These results suggest that activation of Rac1-dependent superoxide generation leads to pancreatic cancer cell proliferation. In pancreatic cancer, inhibition of Rac1 may be a potential therapeutic target.

Mutation

Gene Transfer Techniques

Pancreatic Neoplasms - metabolism

Humans

Pancreatic Neoplasms - pathology

NADPH Oxidases - metabolism

Cell Growth Processes - physiology

Pancreatic Neoplasms - genetics

Reverse Transcriptase Polymerase Chain Reaction

Animals

Mice, Nude

Superoxides - metabolism

rac1 GTP-Binding Protein - antagonists & inhibitors

Adenoviridae - genetics

Cell Line, Tumor

NADPH Oxidases - genetics

Mice

Genes, ras

rac1 GTP-Binding Protein - metabolism

Pancreatic Neoplasms - therapy

rac1 GTP-Binding Protein - genetics

Details

Title: Subtitle: Role of Rac1-dependent NADPH oxidase in the growth of pancreatic cancer
Creators: J Du - Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA, USA
J Liu
B J Smith
M S Tsao
J J Cullen
Resource Type: Journal article
Publication Details: Cancer gene therapy, Vol.18(2), pp.135-143
DOI: 10.1038/cgt.2010.64
PMID: 21037555
PMCID: PMC3058504
NLM abbreviation: Cancer Gene Ther
ISSN: 0929-1903
eISSN: 1476-5500
Publisher: England
Grant note: P01 CA066081 / NCI NIH HHS P01 CA066081-020002 / NCI NIH HHS R21 CA115785-01A1 / NCI NIH HHS R21 CA115785 / NCI NIH HHS I01 BX001318 / BLRD VA
Language: English
Date published: 02/2011
Academic Unit: Biostatistics; Surgery; Radiation Oncology; Holden Comprehensive Cancer Center
Record Identifier: 9983997347702771

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