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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-K_ras_T) that is tumorigenic, were infected with a dominant/negative Rac1 construct (Ad_N17Rac1_). In cells with mutant K-_ras_, Ad_N17Rac1_ decreased rac activity,

decreased superoxide levels and inhibited _in vitro_ growth. However, in the BxPC-3 cell line, Ad_N17Rac1_ did not change rac activity, superoxide levels or _in vitro_ cell growth.

Additionally, Ad_N17Rac1_ 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 Ad_N17Rac1_ 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. Access through your institution Buy or subscribe This is a preview of subscription

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references ACKNOWLEDGEMENTS This study was supported by NIH grants CA115785, CA66081, the Susan L Bader Foundation of Hope, and a Merit Review grant from the Medical Research Service,

Department of Veterans Affairs. AUTHOR INFORMATION Author notes * J Du and J Liu: These two authors contributed equally to this work AUTHORS AND AFFILIATIONS * Department of Radiation

Oncology, University of Iowa College of Medicine, Iowa City, IA, USA J Du, J Liu & J J Cullen * The Holden Comprehensive Cancer Center, Iowa City, IA, USA B J Smith & J J Cullen *

Division of Cellular Molecular Biology, Department of Pathology, Ontario Cancer Institute/Princess Margaret Hospital Toronto, University of Toronto, Ontario, Canada, USA M S Tsao * Veterans

Affairs Medical Center,, Iowa City, IA, USA J J Cullen * Department of Surgery, University of Iowa College of Medicine, Iowa City, IA, USA J J Cullen Authors * J Du View author publications

You can also search for this author inPubMed Google Scholar * J Liu View author publications You can also search for this author inPubMed Google Scholar * B J Smith View author publications

You can also search for this author inPubMed Google Scholar * M S Tsao View author publications You can also search for this author inPubMed Google Scholar * J J Cullen View author

publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to J J Cullen. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no

conflict of interest. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Du, J., Liu, J., Smith, B. _et al._ Role of Rac1-dependent NADPH oxidase in the

growth of pancreatic cancer. _Cancer Gene Ther_ 18, 135–143 (2011). https://doi.org/10.1038/cgt.2010.64 Download citation * Received: 18 March 2010 * Revised: 30 June 2010 * Accepted: 16

August 2010 * Published: 29 October 2010 * Issue Date: February 2011 * DOI: https://doi.org/10.1038/cgt.2010.64 SHARE THIS ARTICLE Anyone you share the following link with will be able to

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initiative KEYWORDS * Rac1 * NADPH oxidase * pancreatic cancer * reactive oxygen species