Therapeutic Targeting Of The Polyamine Pathway And Eif5a1 Hypusination In Endometrial Cancer With Dfmo And Gc7

The polyamines putrescine, spermidine, and spermine are well-characterized oncometabolites upregulated in cancers and drive their proliferation and spread. Endometrial cancers (ECs) express high levels of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis and decreased levels of spermidine/spermine N1-acetyltransferase (SAT1), a key negative regulator of polyamines. In addition, the deoxyhypusine synthase (DHPS) enzyme necessary for spermidine-dependent hypusination of eIF5A1 is highly expressed in ECs. Hypusinated EIF5A1 is needed by cancer cells to support their increased protein translation needs. Collectively, these findings suggest that the polyamine pathway is particularly active and necessary in EC. Here we evaluated the effect of ODC inhibitor difluoromethylornithine (DFMO) and DHPS inhibitor N1-Guanyl-1,7-Diaminoheptane (GC7) alone or in combination on the growth of ECs. GC7 and DFMO were effective in suppressing growth in EC cell lines in vitro as measured by MTS viability and proliferation assays. These effects were accompanied by decreased hypusinated EIF5A1 in treated cells. However, neither compound induced apoptotic cell death when applied singly. We did note that when non-apoptotic inducing doses of DFMO and GC7 were combined, EC cells showed a marked combinatorial decrease in viability, proliferation, and hypusinated EIF5A1 levels. Importantly we found that combined DFMO/GC7 treatment caused apoptotic cell death of EC cells as measured by cleaved PARP. Furthermore, levels of cleaved caspases 3 and 7 were increased in these cells while caspases 5 or 9 were not cleaved. In summary we found for the first time that pharmacologically increased depression of the polyamine pathway as measured by decreased hypusinated EIFA1 can lead to apoptotic cell death in ECs. These data suggest that targeting the polyamine pathway and particularly its role in protein translation through EIF5A1 hypusination may be an effective treatment strategy. Citation Format: HongIm Kim, Chad Schultz, Andre Bachmann, John I. Risinger. Therapeutic targeting of the polyamine pathway and EIF5A1 hypusination in endometrial cancer with DFMO and GC7 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 566.