Antitumor agent PX-12 inhibits HIF-1α protein levels through an Nrf2/PMF-1-mediated increase in spermidine/spermine acetyl transferase

Yon Hui Kim, Amy Coon, Amanda F Baker, Garth Powis

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Purpose: Thioredoxin-1 (Trx-1) redox signaling regulates multiple aspects of cell growth and survival, and elevated tumor levels of Trx-1 have been associated with decreased patient survival. PX-12, an inhibitor of Trx-1 currently in clinical development, has been found to decrease tumor levels of the HIF-1α transcription factor. SSAT1 has been reported to bind to HIF-1α and RACK1, resulting in oxygen-independent HIF-1 ubiquitination and degradation. SSAT2, a related protein, stabilizes the interaction of the VHL protein and elongin C with HIF-1 leading to oxygen-dependent HIF-1α ubiquitination and degradation. We investigated the effects of PX-12 and Trx-1 on SSAT1, SSAT2, and inhibition of HIF-1α. Methods: A panel of cell lines was treated with PX-12 to investigate its effects on SSAT1 and SSAT2 expression, and on HIF-1α protein levels. We also evaluated the regulation of SSAT1 through the Nrf2 and PMF-1, two trans-acting transcription factors. Results: We found that PX-12 increased nuclear Nrf2 activity and antioxidant response element binding. PX-12 also increased the expression of SSAT1 but not SSAT2 in a PMF-1-dependent manner that was independent of Trx-1. Inhibition of Nrf2 or PMF-1 prevented the increase in SSAT1 caused by PX-12. Conclusions: The results show that PX-12, acting independently of Trx-1, increases nuclear Nrf2, which interacts with PMF-1 to increase the expression of SSAT1. The degradation of HIF-1α that results from binding with SSAT1 may explain the decrease in HIF-1α caused by PX-12 and could contribute to the antitumor activity of PX-12.

Original languageEnglish (US)
Pages (from-to)405-413
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume68
Issue number2
DOIs
Publication statusPublished - Aug 2011

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Keywords

  • HIF-1α
  • Nrf2
  • PX-12
  • SSAT1
  • SSAT2
  • Trx-1

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

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