| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Biochemistry and Biophysics |
Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts 02115
The microenvironment of rapidly growing tumors is associated with increasedenergy demand and diminished vascular supply, resulting in focalareas of prominent hypoxia. A number of hypoxia-responsive genes have been associated with growing tumors, and here we demonstrate that the multidrug resistance (MDR1) gene product P-glycoprotein, a Mr 
170,000 transmembrane protein associated with tumor resistance to chemotherapeutics, is induced by ambient hypoxia. Initial studies using quantitative microarray analysis of RNA revealed an 7-fold increase in MDR in epithelial cells exposed to hypoxia (pO2 20 torr, 18 h). These findings were further confirmed at the mRNA and protein level. P-Glycoprotein function was studied by analysis of verapamil-inhibitable efflux of digoxin and rhodamine 123 in intact T84 cells and revealed that hypoxia enhances P-glycoprotein function by as much as 7 ± 0.4-fold over normoxia. Subsequent studies confirmed hypoxia-elicited MDR1 gene induction and increased P-glycoprotein expression in nontransformed, primary cultures of human microvascular endothelial cells, and analysis of multicellular spheroids subjected to hypoxia revealed increased resistance to doxorubicin. Examination of the MDR1 gene identified a binding site for hypoxia inducible factor-1 (HIF-1), and inhibition of HIF-1 expression by antisense oligonucleotides resulted in significant inhibition of hypoxia-inducible MDR1 expression and a nearly complete loss of basal MDR1 expression. Studies using luciferase promoter constructs revealed a significant increase in activity in cells subjected to hypoxia, and such hypoxia inducibility was lost in truncated constructs lacking the HIF-1 site and in HIF-1 binding site mutants. Extensions of these studies also identified a role for Sp1 in this hypoxia response. Taken together, these data indicate that the MDR1 gene is hypoxia responsive, and such results may identify hypoxia-elicited P-glycoprotein expression as a pathway for resistance of some tumors to chemotherapeutics.
This article has been cited by other articles:
|
|
 |
|
  D. Siccardi, K. L. Mumy, D. M. Wall, J. D. Bien, and B. A. McCormick Salmonella enterica serovar Typhimurium modulates P-glycoprotein in the intestinal epithelium Am J Physiol Gastrointest Liver Physiol, June 1, 2008; 294(6): G1392 - G1400. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Callaghan, E. Crowley, S. Potter, and I. D. Kerr P-glycoprotein: So Many Ways to Turn It On J. Clin. Pharmacol., March 1, 2008; 48(3): 365 - 378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Albertella, P. M. Loadman, P. H. Jones, R. M. Phillips, R. Rampling, N. Burnet, C. Alcock, A. Anthoney, E. Vjaters, C. R. Dunk, et al. Hypoxia-Selective Targeting by the Bioreductive Prodrug AQ4N in Patients with Solid Tumors: Results of a Phase I Study Clin. Cancer Res., February 15, 2008; 14(4): 1096 - 1104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. L. Semenza Hypoxia-inducible Factor 1 and Human Cancer ASCO Educational Book, January 1, 2008; 2008(1): 548 - 551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Baek, Y. V. Liu, K. R. McDonald, J. B. Wesley, H. Zhang, and G. L. Semenza Spermidine/Spermine N1-Acetyltransferase-1 Binds to Hypoxia-inducible Factor-1{alpha} (HIF-1{alpha}) and RACK1 and Promotes Ubiquitination and Degradation of HIF-1{alpha} J. Biol. Chem., November 16, 2007; 282(46): 33358 - 33366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Tredan, C. M. Galmarini, K. Patel, and I. F. Tannock Drug Resistance and the Solid Tumor Microenvironment J Natl Cancer Inst, October 3, 2007; 99(19): 1441 - 1454. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kong, M. Scully, C. S. Shelley, and S. P. Colgan Identification of Pur{alpha} as a New Hypoxia Response Factor Responsible for Coordinated Induction of the beta2 Integrin Family J. Immunol., August 1, 2007; 179(3): 1934 - 1941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Rosenberger, J. Khoury, T. Kong, T. Weissmuller, A. M. Robinson, and S. P. Colgan Identification of vasodilator-stimulated phosphoprotein (VASP) as an HIF-regulated tissue permeability factor during hypoxia FASEB J, August 1, 2007; 21(10): 2613 - 2621. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Liu, D. Li, R. Aneja, H. C. Joshi, S. Xie, C. Zhang, and J. Zhou PO2-dependent Differential Regulation of Multidrug Resistance 1 Gene Expression by the c-Jun NH2-terminal Kinase Pathway J. Biol. Chem., June 15, 2007; 282(24): 17581 - 17586. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Wouters, B. Pauwels, F. Lardon, and J. B. Vermorken Review: Implications of In Vitro Research on the Effect of Radiotherapy and Chemotherapy Under Hypoxic Conditions Oncologist, June 1, 2007; 12(6): 690 - 712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Hatle, W. Neveu, O. Dienz, S. Rymarchyk, R. Barrantes, S. Hale, N. Farley, K. M. Lounsbury, J. P. Bond, D. Taatjes, et al. Methylation-Controlled J Protein Promotes c-Jun Degradation To Prevent ABCB1 Transporter Expression Mol. Cell. Biol., April 15, 2007; 27(8): 2952 - 2966. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Prasad, A. Chandra, C. K. Mukhopadhyay, and R. Prasad Unexpected Link between Iron and Drug Resistance of Candida spp.: Iron Depletion Enhances Membrane Fluidity and Drug Diffusion, Leading to Drug-Susceptible Cells Antimicrob. Agents Chemother., November 1, 2006; 50(11): 3597 - 3606. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Wang, S. Ngoi, J. Wang, S. S. Chong, and C. G. L. Lee The Promoter Region of the MDR1 Gene Is Largely Invariant, but Different Single Nucleotide Polymorphism Haplotypes Affect MDR1 Promoter Activity Differently in Different Cell Lines Mol. Pharmacol., July 1, 2006; 70(1): 267 - 276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. B. Rankin, J. E. Tomaszewski, and V. H. Haase Renal cyst development in mice with conditional inactivation of the von hippel-lindau tumor suppressor. Cancer Res., March 1, 2006; 66(5): 2576 - 2583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Brown, R. L. Cowen, C. Debray, A. Eustace, J. T. Erler, F. C. D. Sheppard, C. A. Parker, I. J. Stratford, and K. J. Williams Reversing Hypoxic Cell Chemoresistance in Vitro Using Genetic and Small Molecule Approaches Targeting Hypoxia Inducible Factor-1 Mol. Pharmacol., February 1, 2006; 69(2): 411 - 418. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. H. Wenger, D. P. Stiehl, and G. Camenisch Integration of Oxygen Signaling at the Consensus HRE Sci. Signal., October 18, 2005; 2005(306): re12 - re12. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Lazarowski, H. J. Garcia Rivello, G. L. Vera Janavel, L. A. Cuniberti, P. M. Cabeza Meckert, G. G. Yannarelli, A. Mele, A. J. Crottogini, and R. P. Laguens Cardiomyocytes of Chronically Ischemic Pig Hearts Express the MDR-1 Gene-encoded P-glycoprotein J. Histochem. Cytochem., July 1, 2005; 53(7): 845 - 850. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. A. Louis, K. E. Hamilton, T. Kong, and S. P. Colgan HIF-dependent induction of apical CD55 coordinates epithelial clearance of neutrophils FASEB J, June 1, 2005; 19(8): 950 - 959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Comerford, E. P. Cummins, and C. T. Taylor c-Jun NH2-Terminal Kinase Activation Contributes to Hypoxia-Inducible Factor 1{alpha}-Dependent P-Glycoprotein Expression in Hypoxia Cancer Res., December 15, 2004; 64(24): 9057 - 9061. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Mahadevan and A. F. List Targeting the multidrug resistance-1 transporter in AML: molecular regulation and therapeutic strategies Blood, October 1, 2004; 104(7): 1940 - 1951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. F. Yang, R. T. Poon, J. To, D. W. Ho, and S. T. Fan The Potential Role of Hypoxia Inducible Factor 1{alpha} in Tumor Progression after Hypoxia and Chemotherapy in Hepatocellular Carcinoma Cancer Res., August 1, 2004; 64(15): 5496 - 5503. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kong, H. K. Eltzschig, J. Karhausen, S. P. Colgan, and C. S. Shelley Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of {beta}2 integrin gene expression PNAS, July 13, 2004; 101(28): 10440 - 10445. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Mayer, F. Honecker, L. H. J. Looijenga, and C. Bokemeyer Towards an understanding of the biological basis of response to cisplatin-based chemotherapy in germ-cell tumors Ann. Onc., June 1, 2003; 14(6): 825 - 832. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
