SREBP1 site 1 protease inhibitor PF-429242 suppresses renal cell carcinoma cell growth

Tong-bing Wang,Liu-zheng Zhou,Ai-guo Tang,Mei Geng,Bin-hai Chen,Hua Jin,Qiang Sun,Hao Sun,Gang Shen

doi:10.1038/s41419-021-03999-9

Abstract

Renal cell carcinoma (RCC) cells have increased lipogenesis and cholesterol synthesis. Sterol regulatory element-binding protein-1 (SREBP1) is cleaved by site 1 protease (S1P) to release the transcriptionally active amino-terminal domain. PF-429242 is a potent and competitive S1P inhibitor. We here tested its activity in RCC cells. In established and primary human RCC cells, PF-429242 potently inhibited cell proliferation, migration, and invasion. The S1P inhibitor provoked apoptosis activation in RCC cells. Furthermore, shRNA-mediated S1P silencing or CRISPR/Cas9-induced S1P knockout led to RCC cell growth inhibition and apoptosis activation. Conversely, ectopic overexpression of SREBP1 or S1P augmented RCC cell proliferation and migration. Daily i.v. injection of a single dose of PF-429242 robustly inhibited RCC xenograft growth in severe combined immunodeficiency mice. Additionally, intratumoral injection of S1P shRNA lentivirus inhibited RCC xenograft growth in mice. SREBP1, S1P, and its target gene low density lipoprotein receptor (LDLR) were significantly elevated in human RCC tissues. These results suggest that targeting S1P by PF-429242 inhibited RCC cell growth in vitro and in vivo.

Highlights

Renal cell carcinoma (RCC) is the most common renal malignancy and it accounts for over 2% of all human cancers [1, 2]
CCK-8 assays demonstrated that PF429242 treatment led to less viable RCC1 cells (Fig. 1A)
Medium Lactate dehydrogenase (LDH) release assay results confirmed that PF429242, at 5–25 μM, induced significant RCC1 cell death (Fig. 1B)

Summary

Introduction

Renal cell carcinoma (RCC) is the most common renal malignancy and it accounts for over 2% of all human cancers [1, 2]. Significant progresses have been achieved in current RCC treatments, including radical surgical resection and molecularly-targeted therapies [3,4,5]. 25% of RCC patients can still develop disease progression or metastasis [6, 7]. This could be due to the molecular heterogeneity of RCC [4]. It is extremely important to identify novel prognostic biomarkers and therapeutic targets for this devastating disease. Individualized treatments that assess therapeutic responses and optimize patients prognosis could be developed [4, 5, 8,9,10]

Methods

Results

Conclusion