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Prevention of brefeldin A-induced resistance to teniposide by the proteasome inhibitor MG-132: involvement of NF-kappaB activation in drug resistance.

Publication ,  Journal Article
Lin, ZP; Boller, YC; Amer, SM; Russell, RL; Pacelli, KA; Patierno, SR; Kennedy, KA
Published in: Cancer Res
July 15, 1998

Brefeldin A, an agent that disrupts protein transport from the endoplasmic reticulum to the Golgi, induces the expression of GRP78 and the activation of nuclear factor (NF)-kappaB in cells. Treatment of cells with brefeldin A causes the development of resistance to topoisomerase II-directed agents, such as etoposide and doxorubicin. In this study, we show that treatment of EMT6 mouse mammary tumor cells with brefeldin A strongly induces GRP78 mRNA (8.5-fold) and resistance to teniposide (VM26). Treatment with okadaic acid causes a minor increase in GRP78 mRNA (2.1-fold) yet still induces resistance to VM26 as effectively as brefeldin A. In contrast, cells treated with castanospermine show a moderate increase in GRP78 mRNA (3.9-fold) but no resistance to VM26. These data imply that GRP78 induction does not mediate the development of drug resistance. An alternative mechanism of drug resistance may involve activation of the transcription factor, NF-kappaB, and we show that both brefeldin A and okadaic acid activate NF-kappaB in EMT6 cells. Furthermore, we demonstrate that treatment with the proteasome inhibitor MG-132 blocks the activation of NF-kappaB and prevents the development of resistance to VM26 induced by brefeldin A. Collectively, these results suggest that the resistance to VM26 in EMT6 cells treated with brefeldin A is mediated by the activation of NF-kappaB rather than the induction of GRP78. Our results also suggest that inhibition of NF-kappaB activation in tumor cells may increase the efficacy of topoisomerase II-directed agents in chemotherapy.

Duke Scholars

Published In

Cancer Res

ISSN

0008-5472

Publication Date

July 15, 1998

Volume

58

Issue

14

Start / End Page

3059 / 3065

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Teniposide
  • Protein Synthesis Inhibitors
  • Proteasome Endopeptidase Complex
  • Oncology & Carcinogenesis
  • Neoplasm Proteins
  • NF-kappa B
  • Multienzyme Complexes
  • Molecular Chaperones
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lin, Z. P., Boller, Y. C., Amer, S. M., Russell, R. L., Pacelli, K. A., Patierno, S. R., & Kennedy, K. A. (1998). Prevention of brefeldin A-induced resistance to teniposide by the proteasome inhibitor MG-132: involvement of NF-kappaB activation in drug resistance. Cancer Res, 58(14), 3059–3065.
Lin, Z. P., Y. C. Boller, S. M. Amer, R. L. Russell, K. A. Pacelli, S. R. Patierno, and K. A. Kennedy. “Prevention of brefeldin A-induced resistance to teniposide by the proteasome inhibitor MG-132: involvement of NF-kappaB activation in drug resistance.Cancer Res 58, no. 14 (July 15, 1998): 3059–65.
Lin ZP, Boller YC, Amer SM, Russell RL, Pacelli KA, Patierno SR, et al. Prevention of brefeldin A-induced resistance to teniposide by the proteasome inhibitor MG-132: involvement of NF-kappaB activation in drug resistance. Cancer Res. 1998 Jul 15;58(14):3059–65.
Lin ZP, Boller YC, Amer SM, Russell RL, Pacelli KA, Patierno SR, Kennedy KA. Prevention of brefeldin A-induced resistance to teniposide by the proteasome inhibitor MG-132: involvement of NF-kappaB activation in drug resistance. Cancer Res. 1998 Jul 15;58(14):3059–3065.

Published In

Cancer Res

ISSN

0008-5472

Publication Date

July 15, 1998

Volume

58

Issue

14

Start / End Page

3059 / 3065

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Teniposide
  • Protein Synthesis Inhibitors
  • Proteasome Endopeptidase Complex
  • Oncology & Carcinogenesis
  • Neoplasm Proteins
  • NF-kappa B
  • Multienzyme Complexes
  • Molecular Chaperones
  • Mice