| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 279, Issue 33, 34643-34654, August 13, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Departments of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and UCLA, Los Angeles, California 90073
One reason why pancreatic cancer is so aggressive and unresponsive to treatments is its resistance to apoptosis. We report here that reactive oxygen species (ROS) are a prosurvival, antiapoptotic factor in pancreatic cancer cells. Human pancreatic adenocarcinoma MIA PaCa-2 and PANC-1 cells generated ROS, which was stimulated by growth factors (serum, insulin-like growth factor I, or fibroblast growth factor-2). Growth factors also stimulated membrane NAD(P)H oxidase activity in these cells. Both intracellular ROS and NAD(P)H oxidase activity were inhibited by antioxidants tiron and N-acetylcysteine and the inhibitor of flavoprotein-dependent oxidases, diphenylene iodonium, but not by inhibitors of various other ROS-generating enzymes. Using Rho0 cells deficient in mitochondrial DNA, we showed that a nonmitochondrial NAD(P)H oxidase is a major source of growth factor-induced ROS in pancreatic cancer cells. Among proteins that have been implicated in NAD(P)H oxidase activity, MIA PaCa-2 and PANC-1 cells do not express the phagocytic gp91phox subunit but express several nonphagocytic oxidase (NOX) isoforms. Transfection with Nox4 antisense oligonucleotide inhibited NAD(P)H oxidase activity and ROS production in MIA PaCa-2 and PANC-1 cells. Inhibiting ROS with the antioxidants, Nox4 antisense, or MnSOD overexpression all stimulated apoptosis in pancreatic cancer cells as measured by internucleosomal DNA fragmentation, phosphatidylserine externalization, cytochrome c release, and effector caspase activation. The results show that growth factor-induced ROS produced by NAD(P)H oxidase (probably Nox4) protect pancreatic cancer cells from apoptosis. This mechanism may play an important role in pancreatic cancer resistance to treatment and thus represent a novel therapeutic target.
Received for publication, January 6, 2004 , and in revised form, May 14, 2004.
* This work was supported by the Department of Veterans Affairs Merit Review and National Institutes of Health Grant DK-59936 (to A. S. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
These authors contributed equally to this work.
To whom correspondence should be addressed: VA Greater Los Angeles Healthcare System, West Los Angeles Healthcare Center, Bldg. 258, Rm. 340, 11301 Wilshire Blvd., Los Angeles, CA 90073. Fax: 310-268-4578; E-mail: agukovsk{at}ucla.edu.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  K. Chen, M. T. Kirber, H. Xiao, Y. Yang, and J. F. Keaney Jr. Regulation of ROS signal transduction by NADPH oxidase 4 localization J. Cell Biol., June 30, 2008; 181(7): 1129 - 1139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Kumar, S. Koul, L. Khandrika, R. B. Meacham, and H. K. Koul Oxidative Stress Is Inherent in Prostate Cancer Cells and Is Required for Aggressive Phenotype Cancer Res., March 15, 2008; 68(6): 1777 - 1785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L.T. Teoh, W. Sun, B. J. Smith, L. W. Oberley, and J. J. Cullen Modulation of Reactive Oxygen Species in Pancreatic Cancer Clin. Cancer Res., December 15, 2007; 13(24): 7441 - 7450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Datla, H. Peshavariya, G. J. Dusting, K. Mahadev, B. J. Goldstein, and F. Jiang Important Role of Nox4 Type NADPH Oxidase in Angiogenic Responses in Human Microvascular Endothelial Cells In Vitro Arterioscler. Thromb. Vasc. Biol., November 1, 2007; 27(11): 2319 - 2324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gong, S. Hay, K. R. Marshall, A. W. Munro, and N. S. Scrutton DNA Binding Suppresses Human AIF-M2 Activity and Provides a Connection between Redox Chemistry, Reactive Oxygen Species, and Apoptosis J. Biol. Chem., October 12, 2007; 282(41): 30331 - 30340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Edderkaoui, P. Hong, J. K. Lee, S. J. Pandol, and A. S. Gukovskaya Insulin-like Growth Factor-I Receptor Mediates the Prosurvival Effect of Fibronectin J. Biol. Chem., September 14, 2007; 282(37): 26646 - 26655. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shinohara, W.-H. Shang, M. Kubodera, S. Harada, J. Mitsushita, M. Kato, H. Miyazaki, H. Sumimoto, and T. Kamata Nox1 Redox Signaling Mediates Oncogenic Ras-induced Disruption of Stress Fibers and Focal Adhesions by Down-regulating Rho J. Biol. Chem., June 15, 2007; 282(24): 17640 - 17648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Block, Y. Gorin, P. Hoover, P. Williams, T. Chelmicki, R. A. Clark, T. Yoneda, and H. E. Abboud NAD(P)H Oxidases Regulate HIF-2{alpha} Protein Expression J. Biol. Chem., March 16, 2007; 282(11): 8019 - 8026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Bedard and K.-H. Krause The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology Physiol Rev, January 1, 2007; 87(1): 245 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. N. Criddle, S. Gillies, H. K. Baumgartner-Wilson, M. Jaffar, E. C. Chinje, S. Passmore, M. Chvanov, S. Barrow, O. V. Gerasimenko, A. V. Tepikin, et al. Menadione-induced Reactive Oxygen Species Generation via Redox Cycling Promotes Apoptosis of Murine Pancreatic Acinar Cells J. Biol. Chem., December 29, 2006; 281(52): 40485 - 40492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Du, D. H. Daniels, C. Asbury, S. Venkataraman, J. Liu, D. R. Spitz, L. W. Oberley, and J. J. Cullen Mitochondrial Production of Reactive Oxygen Species Mediate Dicumarol-induced Cytotoxicity in Cancer Cells J. Biol. Chem., December 8, 2006; 281(49): 37416 - 37426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Tammali, K. V. Ramana, S. S. Singhal, S. Awasthi, and S. K. Srivastava Aldose Reductase Regulates Growth Factor-Induced Cyclooxygenase-2 Expression and Prostaglandin E2 Production in Human Colon Cancer Cells Cancer Res., October 1, 2006; 66(19): 9705 - 9713. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. McKallip, W. Jia, J. Schlomer, J. W. Warren, P. S. Nagarkatti, and M. Nagarkatti Cannabidiol-Induced Apoptosis in Human Leukemia Cells: A Novel Role of Cannabidiol in the Regulation of p22phox and Nox4 Expression Mol. Pharmacol., September 1, 2006; 70(3): 897 - 908. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Sinha, A. Singh, V. Satchidanandam, and K. Natarajan Impaired Generation of Reactive Oxygen Species during Differentiation of Dendritic Cells (DCs) by Mycobacterium tuberculosis Secretory Antigen (MTSA) and Subsequent Activation of MTSA-DCs by Mycobacteria Results in Increased Intracellular Survival J. Immunol., July 1, 2006; 177(1): 468 - 478. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Pagano and M. J. Haurani Vascular Cell Locomotion: Osteopontin, NADPH Oxidase, and Matrix Metalloproteinase-9 Circ. Res., June 23, 2006; 98(12): 1453 - 1455. [Full Text] [PDF]
|
|
|
|
|
|
Y. Gong, H. Sohn, L. Xue, G. L. Firestone, and L. F. Bjeldanes 3,3'-Diindolylmethane Is a Novel Mitochondrial H+-ATP Synthase Inhibitor that Can Induce p21Cip1/Waf1 Expression by Induction of Oxidative Stress in Human Breast Cancer Cells. Cancer Res., May 1, 2006; 66(9): 4880 - 4887. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Fernandez, T. P. Miller, C. Denoyelle, J. A. Esteban, W.-H. Tang, A. L. Bengston, and M. S. Soengas Chemical Blockage of the Proteasome Inhibitory Function of Bortezomib: IMPACT ON TUMOR CELL DEATH J. Biol. Chem., January 13, 2006; 281(2): 1107 - 1118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Edderkaoui, P. Hong, E. C. Vaquero, J. K. Lee, L. Fischer, H. Friess, M. W. Buchler, M. M. Lerch, S. J. Pandol, and A. S. Gukovskaya Extracellular matrix stimulates reactive oxygen species production and increases pancreatic cancer cell survival through 5-lipoxygenase and NADPH oxidase Am J Physiol Gastrointest Liver Physiol, December 1, 2005; 289(6): G1137 - G1147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hu, S. P. RamachandraRao, S. Siva, C. Valancius, Y. Zhu, K. Mahadev, I. Toh, B. J. Goldstein, M. Woolkalis, and K. Sharma Reactive oxygen species production via NADPH oxidase mediates TGF-{beta}-induced cytoskeletal alterations in endothelial cells Am J Physiol Renal Physiol, October 1, 2005; 289(4): F816 - F825. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Kobayashi, F. A. DeLano, and G. W. Schmid-Schonbein Oxidative Stress Promotes Endothelial Cell Apoptosis and Loss of Microvessels in the Spontaneously Hypertensive Rats Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2114 - 2121. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Stapelberg, N. Gellert, E. Swettenham, M. Tomasetti, P. K. Witting, A. Procopio, and J. Neuzil {alpha}-Tocopheryl Succinate Inhibits Malignant Mesothelioma by Disrupting the Fibroblast Growth Factor Autocrine Loop: MECHANISM AND THE ROLE OF OXIDATIVE STRESS J. Biol. Chem., July 8, 2005; 280(27): 25369 - 25376. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. T. Teoh, P. V. Turner, and D. H. Evans Tumorigenic Poxviruses Up-Regulate Intracellular Superoxide To Inhibit Apoptosis and Promote Cell Proliferation J. Virol., May 1, 2005; 79(9): 5799 - 5811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Djordjevic, R. S. BelAiba, S. Bonello, J. Pfeilschifter, J. Hess, and A. Gorlach Human Urotensin II Is a Novel Activator of NADPH Oxidase in Human Pulmonary Artery Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., March 1, 2005; 25(3): 519 - 525. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
