Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 2, pp 405–413

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
Original Article

DOI: 10.1007/s00280-010-1500-0

Cite this article as:
Kim, Y.H., Coon, A., Baker, A.F. et al. Cancer Chemother Pharmacol (2011) 68: 405. doi:10.1007/s00280-010-1500-0

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.

Keywords

PX-12 SSAT1 SSAT2 Nrf2 Trx-1 HIF-1α 

Abbreviations

ARE

Antioxidant response element

Ask-1

Apoptosis signal–regulating kinase-1

HIF-1α

Hypoxia-inducible factor-1alpha

Keap1

Kelch-like ECH-associated protein 1

NAD(P)H

Nicotinamide adenine dinucleotide phosphate oxidase

NQO1

NADPH dehydrogenase, quinone 1

Nrf2

Nuclear factor erythroid-derived 2(NF-E2)–related factor 2

PMF-1

Polyamine modulated factor-1

PRE

Positive regulatory element

PTEN

Phosphatase and tensin homolog

pVHL

Von Hippel-Lindau protein

PX-12

1-Methylpropyl 2-imidazolyl disulfide

RACK1

Receptor for activated C kinase 1

RT–PCR

Reverse transcription-polymerase chain reaction

siRNA

Small interfering RNA

SSAT1

Spermidine/spermine N(1)-acetyltransferase 1

SSAT2

Spermidine/spermine N(1)-acetyltransferase 2

Trx-1

Thioredoxin-1

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Yon Hui Kim
    • 1
  • Amy Coon
    • 2
  • Amanda F. Baker
    • 2
  • Garth Powis
    • 1
  1. 1.Department of Experimental TherapeuticsThe University of Texas M. D. Anderson Cancer CenterHoustonUSA
  2. 2.Arizona Cancer Center, University of ArizonaTucsonUSA

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