© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 1, 18-23,
January 5, 2000
© 2000 Oxford University Press
Epigenetic Determinants of Resistance to Etoposide Regulation of Bcl-xL and Bax by Tumor Microenvironmental Factors
Affiliation of authors: Cancer Research Campaign Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester, U.K.
Correspondence to: Caroline Dive, Ph.D., Cancer Research Campaign Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester, G38 Stopford Bldg., Oxford Rd., Manchester M13 9PT, U.K. (e-mail: cdive{at}man.ac.uk).
BACKGROUND: Epigenetic factors (i.e., alterations of gene activity not involving mutations), as
well as genetic changes in surviving cancer cells, may play an important role in drug resistance
following cancer chemotherapy—a common cause of tumor relapse. Bcl-2 family proteins
are central to the regulation of apoptotic cell death and modulate drug sensitivity. We investigated
how survival signals in the cellular microenvironment affect the expression, protein conformation,
and protein-protein interactions of the Bcl-2 family proteins Bax and Bcl-xL and how
changes in response to microenvironmental signals alter the response of cancer cells to the drug
etoposide. METHODS: JLP119 human B-lymphoma cells were treated with etoposide (40 µM) and then cultured in the presence of an activating anti-CD40 antibody, vascular
cellular adhesion molecule-1 (VCAM-1)—to activate VLA-4 (
4ß1) integrin, and
interleukin 4. Cell fate was monitored after etoposide treatment with or without these
microenvironmental signals. Bcl-xL gene transcription and protein levels of Bcl-xL and Bax were measured by northern and western blotting, respectively. Nuclear
translocation of transcription factor NF-
B was monitored by immunofluorescence and
inhibited by (E)-capsaicin. Bax conformation and Bax-Bcl-xL interactions were
monitored by immunofluorescence and immunoprecipitation, respectively. RESULTS:
Microenvironmental survival signals produced statistically significant reductions in
etoposide-induced apoptotic cell death, from 84.6% (95% confidence interval
[CI] = 76.7%-92.4%) to 21.3% (95% CI =
19.5%-23.0%); P<.001. Activation of surface protein CD40 increased
Bcl-xL protein levels via an (E)-capsaicin-inhibitable activation of NF-B; i.e.,
(E)-capsaicin restored etoposide sensitivity. Interleukin 4 had no effect on Bcl-xL
protein levels but accelerated the increase in Bcl-xL protein associated with CD40
activation. VCAM-1- and interleukin 4-mediated signals diminished conformational changes in
Bax protein and prevented the etoposide-induced disruption of constitutive Bax-Bcl-xL binding. CONCLUSIONS: Microenvironmental factors reduce the sensitivity of a B-cell
lymphoma to etoposide in vitro by modulating the expression and functions of Bax and
Bcl-xL. This interaction may provide a paradigm for epigenetically induced drug
resistance in other tumors.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Z. Zeng, Y. Xi Shi, I. J. Samudio, R.-Y. Wang, X. Ling, O. Frolova, M. Levis, J. B. Rubin, R. R. Negrin, E. H. Estey, et al. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML Blood, June 11, 2009; 113(24): 6215 - 6224. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kobune, H. Chiba, J. Kato, K. Kato, K. Nakamura, Y. Kawano, K. Takada, R. Takimoto, T. Takayama, H. Hamada, et al. Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism Mol. Cancer Ther., June 1, 2007; 6(6): 1774 - 1784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Olson, L. C. Burkly, D. R. Leone, B. M. Dolinski, and R. R. Lobb Anti-{alpha}4 integrin monoclonal antibody inhibits multiple myeloma growth in a murine model Mol. Cancer Ther., January 1, 2005; 4(1): 91 - 99. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Gu, L. Espana, O. Mendez, A. Torregrosa, and A. Sierra Organ-selective chemoresistance in metastasis from human breast cancer cells: inhibition of apoptosis, genetic variability and microenvironment at the metastatic focus Carcinogenesis, December 1, 2004; 25(12): 2293 - 2301. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Ozvaran, X. X. Cao, S. D. Miller, B. A. Monia, W. K. Hong, and W. R. Smythe Antisense oligonucleotides directed at the bcl-xl gene product augment chemotherapy response in mesothelioma Mol. Cancer Ther., May 1, 2004; 3(5): 545 - 550. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. R. Smythe, I. Mohuiddin, M. Ozveran, and X. X. Cao Antisense therapy for malignant mesothelioma with oligonucleotides targeting the bcl-xl gene product J. Thorac. Cardiovasc. Surg., June 1, 2002; 123(6): 1191 - 1198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Lansiaux, M. Facompre, N. Wattez, M.-P. Hildebrand, C. Bal, D. Demarquay, O. Lavergne, D. C. H. Bigg, and C. Bailly Apoptosis Induced by the Homocamptothecin Anticancer Drug BN80915 in HL-60 Cells Mol. Pharmacol., September 1, 2001; 60(3): 450 - 461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Mudry, J. E. Fortney, T. York, B. M. Hall, and L. F. Gibson Stromal cells regulate survival of B-lineage leukemic cells during chemotherapy Blood, September 1, 2000; 96(5): 1926 - 1932. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. H. Shoemaker Genetic and Epigenetic Factors in Anticancer Drug Resistance J Natl Cancer Inst, January 5, 2000; 92(1): 4 - 5. [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. Mercatante, C. D. Bortner, J. A. Cidlowski, and R. Kole Modification of Alternative Splicing of Bcl-x Pre-mRNA in Prostate and Breast Cancer Cells. ANALYSIS OF APOPTOSIS AND CELL DEATH J. Biol. Chem., May 4, 2001; 276(19): 16411 - 16417. [Abstract] [Full Text] [PDF]
|
|