Abstract
SUMO-specific protease 1 (SENP1), a member of the de-SUMOylation protease family, is elevated in prostate cancer (PCa) cells and is involved in PCa pathogenesis. Momordin Ιc (Mc), a natural pentacyclic triterpenoid, inhibited SENP1 in vitro, as reflected by reduced SENP1C-induced cleavage of SUMO2-ΔRanGAP1. Mc also altered the thermal stability of SENP1 in a newly developed cellular thermal shift assay, indicating that Mc directly interacts with SENP1 in PCa cells. Consistent with SENP1 inhibition, Mc increased SUMOylated protein levels, which was further confirmed by the accumulation of two known SUMOylated proteins, hypoxia inducible factor-1a and nucleus accumbens associated protein 1 in PC3 cells. Compared to LNCaP and normal prostate epithelial RWPE-1 cells, PC3 cells had higher levels of SENP1 mRNA and were more sensitive to Mc-induced growth inhibition. Mc also reduced SENP1 mRNA levels in PCa cells. Overexpression of SENP1 rescued PC3 cells from Mc-induced apoptosis. Finally, Mc suppressed cell proliferation and induced cell death in vivo in a xenograft PC3 tumor mouse model. These findings demonstrate that Mc is a novel SENP1 inhibitor with potential therapeutic value for PCa. Investigation of other pentacyclic triterpenoids may aid in the development of novel SENP1 inhibitor drugs.
Highlights
Prostate cancer (PCa) is the most frequently diagnosed cancer, and the second leading cause of cancer-related death, in men, with an estimated 27,540 deaths worldwide in 2015 [1]
In a screening to identify natural compounds with SENP1 inhibitor activity, we found that Momordin Ιc (Mc) (Figure 1A), a natural pentacyclic triterpenic compound, markedly inhibited SENP1C-mediated cleavage of SUMO2∆RanGAP1 in an in vitro deSUMOylation assay (Figure 1B)
As only SENP1C contained the appropriate catalytic domain, we examined whether Mc inhibited the activity of full-length SENP1 in cells
Summary
Prostate cancer (PCa) is the most frequently diagnosed cancer, and the second leading cause of cancer-related death, in men, with an estimated 27,540 deaths worldwide in 2015 [1]. The use of the prostate-specific antigen (PSA) blood test for screening has dramatically increased PCa incidence rates in China [2]. It is crucial to develop novel strategies to treat prostate cancer. SUMOylation regulates many cellular processes, including protein-protein interactions, transcription, protein localization, cell cycle progression, DNA replication and repair, chromatin organization, and RNA metabolism [4,5,6]. SUMOylation is catalyzed by SUMO-specific activating (E1), conjugating (E2), and ligating (E3) enzymes [7]. SUMO-specific www.impactjournals.com/oncotarget proteases (SENPs), which include 6 members named SENP1, SENP2, SENP3, SENP5, SENP6, and SENP7, reverse SUMOylation. SENP1 is a nuclear protease that, when overexpressed, deconjugates a large number of SUMOylated proteins. SENP1 is considered a potential therapeutic target for PCa
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