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Proteasome inhibition induces a p38 MAPK pathway-dependent antiapoptotic program via Nrf2 in thyroid cancer cells

Zhen-Xian Du1, Ying Yan, Hai-Yan Zhang

  • 1Department of Endocrinology and Metabolism, the First Affiliated Hospital, China Medical University, Shenyang 110001, China. dzx_doctor@hotmail.com

The Journal of Clinical Endocrinology and Metabolism
|February 25, 2011
PubMed
Abstract

Insights

Proteasome inhibitors activate a survival pathway in thyroid cancer cells involving Nuclear factor erythroid 2-related factor 2 (Nrf2) and p38 MAPK. This pathway, which includes glutathione production, helps cancer cells resist treatment.

Area of Science:

  • Cellular Biology
  • Cancer Research
  • Molecular Oncology

Background:

  • Thyroid cancer cells exhibit cytotoxic responses to proteasome inhibition, partly due to reactive oxygen species scavenging via glutathione production.
  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor regulating cytoprotective genes like glutamate cysteine ligase (GCLC).

Purpose of the Study:

  • To investigate the role of Nrf2 in GCLC induction and thyroid cancer cell cytotoxicity under proteasome inhibition.
  • To elucidate the involvement of the p38 MAPK pathway in Nrf2-mediated responses to proteasome inhibitors.

Main Methods:

  • Immunocytochemistry and Western blot analyzed Nrf2 expression and distribution.
  • Gene manipulation (Nrf2 plasmid/siRNA, p38 MAPK siRNA) and molecular assays (flow cytometry, spectrophotometry, real-time RT-PCR) assessed cellular responses.

Main Results:

  • Proteasome inhibition led to Nrf2 accumulation and nuclear translocation, partially reducing cytotoxicity via GCLC induction.
  • Nrf2 nuclear translocation was dependent on p38 MAPK; inhibiting p38 MAPK enhanced proteasome inhibitor cytotoxicity by suppressing Nrf2 transactivation.

Conclusions:

  • Proteasome inhibitors activate an antiapoptotic survival mechanism in thyroid cancer cells.
  • This survival program is mediated by p38 MAPK and involves the transcriptional activity of Nrf2.

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