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

Cancer Gene Therapy volume 18, pages 135–143 (2011)Cite this article

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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.

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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.

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Author notes

  1. J Du and J Liu: These two authors contributed equally to this work

Authors and Affiliations

  1. Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA, USA

    J Du, J Liu & J J Cullen

  2. The Holden Comprehensive Cancer Center, Iowa City, IA, USA

    B J Smith & J J Cullen

  3. Division of Cellular Molecular Biology, Department of Pathology, Ontario Cancer Institute/Princess Margaret Hospital Toronto, University of Toronto, Ontario, Canada, USA

    M S Tsao

  4. Veterans Affairs Medical Center,, Iowa City, IA, USA

    J J Cullen

  5. Department of Surgery, University of Iowa College of Medicine, Iowa City, IA, USA

    J J Cullen

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  1. J Du
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Correspondence to J J Cullen.

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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

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