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Cited by 45Cancer, Hypoxia, and MetabolismRedox biology and oxidative stressGenomics, phytochemicals, and oxidative stress

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, Yon Hui, Coon, Amy, Baker, Amanda F., Powis, Garth·2011·Cancer Chemotherapy and Pharmacology
DOI 10.1007/s00280-010-1500-0PMC PMC3107346
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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.

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  • PX-12 promotes HIF-1α ubiquitination through induction of spermidine/spermine N1-acetyltransferase 1, independently of Trx-1 inhibition.

    “Mechanistic studies suggest that PX-12 promotes HIF-1α ubiquitination through induction of spermidine/spermine N1-acetyltransferase 1, independently of Trx-1 inhibition [358].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [358]

    The Results and Discussion report that PX-12 increases SSAT1 and lowers HIF-1α independently of Trx-1. The Discussion describes SSAT1-mediated HIF-1α ubiquitination as a previously reported mechanism, but does not show that PX-12 promotes ubiquitination; its finding that proteasome inhibition did not prevent the HIF-1α decrease suggests another degradation mechanism may be involved. No page numbers are available in our copy. (LLM, conf=0.88)

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References 32 · Cited by 45

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Authors
Kim, Y. H., Coon, A., Baker, A. F., & Powis, G.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • University of Arizona (US)
Corresponding author
Kim, Yon Hui
ORCID
Venue
Cancer Chemotherapy and Pharmacology
Publisher
Springer Science and Business Media LLC
Published
2010-11-11
Volume
68
Issue
2
Pages
405-413
ISSN
  • 0344-5704 (ISSN-L)
  • 1432-0843
DOI
10.1007/s00280-010-1500-0
PMC
PMC3107346
OpenAlex
W2032370690
Cited by
45
References
32
Citations by year
2026: 3 · 2025: 1 · 2024: 2 · 2022: 1 · 2021: 1 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 8 · 2015: 2 · 2014: 4 · 2013: 1 · 2012: 4
FWCI
0.81
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Cancer Chemotherapy and Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (CA109552., R01CA077204, R01CA098920, CA077204, R01CA129616, P01CA109552, CA129616)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Keywords
PX-12, HIF-1α, Nrf2, thioredoxin-1, HIF-1α degradation, anticancer agents, redox signaling, transcription factors
MeSH terms
Diamine N-Acetyltransferase, Acetyltransferases, Antineoplastic Agents, Antioxidants, Cell Line, Transformed, Disulfides, DNA-Binding Proteins, Humans, Imidazoles, Isoenzymes, Neoplasm Proteins, Neoplasms, RNA, Messenger, Thioredoxins, Transcription Factors, Signal Transduction, Cell Hypoxia, Gene Expression Regulation, Neoplastic, Response Elements, Gene Silencing, RNA, Small Interfering, Cell Line, Tumor, NF-E2-Related Factor 2, Hypoxia-Inducible Factor 1, alpha Subunit

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