Work

Identification of potent SENP1 inhibitors that inactivate SENP1/JAK2/STAT signaling pathway and overcome platinum drug resistance in ovarian cancer

Year: 2021

Type: article

Abstract: Identification of potent SENP1 inhibitors that inactivate SENP1/JAK2/STAT signaling pathway and overcome platinum drug resistance in ovarian cancerDear Editor, Sentrin-specific protease 1 (SENP1) is a protease that is important for tumor development and drug resistance.1,2 Our recent discovery indicates that SENP1 is critical for Janus kinase/signal transducers and activators of transcription (JAK2/STAT) signaling by regulating JAK2 activity through deSUMOylation. 1 Therefore, targeting SENP1 is a promising approach for cancer therapy and many efforts have been invested into developing SENP1 inhibitors.3 Momordin Ιc (Mc) is a natural compound that inhibits SENP1 with higher IC 50 .4 To identify potent SENP1 inhibitors, we conducted a drug synergy screening by using a collection of Mc natural compound analogues (Figure 1A).This screening is based on our discovery that overexpressed SENP1 contributes to cisplatin resistance in ovarian cancer (OC) and inhibition of SENP1 by Mc exhibits the great synergistic effects with cisplatin to inhibit resistant OC cancer cells IGROV1 CR. 1 Thus, if one Mc analogue exhibits synergy with cisplatin in resistant cells, it may target SENP1.The screening identified ursolic acid (UA) and triptolide that re-sensitized resistant cells to cisplatin with lower IC 50 (UA: 0.86 μM; triptolide: 1.37 μM) (Figure 1B), suggesting a good synergy with cisplatin.Interestingly, triptolide was reported to inhibit SENP1, 5 further supporting the feasibility of the screening strategy.We next examined JAK2 SUMOylation in cells treated with Mc or UA.JAK2 SUMOylation levels were significantly increased upon treatments, indicating that UA and Mc inhibit SENP1 (Figure 1C,D).The IC 50 of UA (0.24 μM) is much lower than Mc (31.76 μM) (Figure 1E).In vitro deSUMOylation assay confirmed the inhibition of UA on SENP1 with IC 50 at 0.0064 μM, compared to 19.91 μM by Mc (Figure 1F-H).Cellular thermal shift assay, which is used to compare the thermal stabilization of a protein in ligand-free and ligand-bound states, 6,7 showed that at higher temperatures SENP1 protein was stabilized in cells

Source: Clinical and Translational Medicine

DOI: 10.1002/ctm2.649