Antitumor agent PX-12 inhibits HIF-1α protein levels through an Nrf2/PMF-1-mediated increase in spermidine/spermine acetyl transferase
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- Kim, Y.H., Coon, A., Baker, A.F. et al. Cancer Chemother Pharmacol (2011) 68: 405. doi:10.1007/s00280-010-1500-0
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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.
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.
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.
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.
KeywordsPX-12 SSAT1 SSAT2 Nrf2 Trx-1 HIF-1α
Antioxidant response element
Apoptosis signal–regulating kinase-1
Kelch-like ECH-associated protein 1
Nicotinamide adenine dinucleotide phosphate oxidase
NADPH dehydrogenase, quinone 1
Nuclear factor erythroid-derived 2(NF-E2)–related factor 2
Polyamine modulated factor-1
Positive regulatory element
Phosphatase and tensin homolog
Von Hippel-Lindau protein
1-Methylpropyl 2-imidazolyl disulfide
Receptor for activated C kinase 1
Reverse transcription-polymerase chain reaction
Small interfering RNA
Spermidine/spermine N(1)-acetyltransferase 1
Spermidine/spermine N(1)-acetyltransferase 2