Pharmacological targeting of polyamine and hypusine biosynthesis reduces tumour activity of endometrial cancer

Abstract

Endometrial cancer (EC) is a common and deadly cancer in women and novel therapeutic approaches are urgently needed. Polyamines (putrescine, spermidine, spermine) are critical for mammalian cell proliferation and MYC coordinately regulates polyamine metabolism through ornithine decarboxylase (ODC). ODC is a MYC target gene and rate-limiting enzyme of polyamine biosynthesis and the FDA-approved anti-protozoan drug α-difluoromethylornithine (DFMO) inhibits ODC activity and induces polyamine depletion that leads to tumour growth arrest. Spermidine is required for the hypusine-dependent activation of eukaryotic translation initiation factors 5A1 (eIF5A1) and 5A2 (eIF5A2) and connects the MYC/ODC-induced deregulation of spermidine to eIF5A1/2 protein translation, which is increased during cancer cell proliferation. We show that eIF5A1 is significantly upregulated in EC cells compared to control cells (p=.000038) and that combined pharmacological targeting of ODC and eIF5A hypusination with cytostatic drugs DFMO and N1-guanyl-1,7-diaminoheptane (GC7), respectively, reduces eIF5A1 activation and synergistically induces apoptosis in EC cells. In vivo, DFMO/GC7 suppressed xenografted EC tumour growth in mice more potently than each drug alone compared to control (p=.002) and decreased putrescine (p=.045) and spermidine levels in tumour tissues. Our data suggest DFMO and GC7 combination therapy may be useful in the treatment or prevention of EC.

Keywords:

• Endometrial cancer
• polyamines
• ODC
• hypusine
• eIF5A1
• DHPS
• DFMO
• GC7
• cell death
• in vivo tumour xenografts

Acknowledgements

We thank Dr. Patrick Woster (Medical University of South Carolina, Charleston, SC) for providing DFMO and Dr. Asgi Fazleabas (Michigan State University) for non-tumorigenic 12Z endometrial epithelial cells. We are grateful to Dr. Otto Phanstiel (University of Central Florida, Orlando, FL) for providing dansylated spermidine and 1,7-diaminoheptane standards and Mr. Zachary Madaj (Van Andel Research Institute, Bioinformatics and Biostatistics Core, Grand Rapids, MI) for helpful advice with SynergyFinder data interpretation.

Authors contributions

Conception and design: A.S. Bachmann, J.I. Risinger; development of methodology: H.I. Kim, C.R. Schultz and D. Geerts; acquisition of data: H.I. Kim, C.R. Schultz and D. Geerts; analysis and interpretation of data: all authors; writing, review and/or revision of the manuscript: all authors.

Disclosure statement

A.S. Bachmann is the sole inventor of a U.S. patent (US 9,072,778) issued on 7 July 2015 entitled ‘Treatment Regimen for N-Myc, C-Myc and L-Myc amplified and overexpressed tumors’. No potential conflicts of interest were disclosed by the other authors.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This study was performed with Spectrum Health-Michigan State University Alliance Corporation funds and internal Michigan State University funds to A. S. Bachmann and J. I. Risinger.