A Novel L-Phenylalanine Dipeptide Inhibits the Growth and Metastasis of Prostate Cancer Cells via Targeting DUSP1 and TNFSF9

Abstract

Prostate cancer (PCa) is a common malignant cancer of the urinary system. Drug therapy, chemotherapy, and radical prostatectomy are the primary treatment methods, but drug resistance and postoperative recurrence often occur. Therefore, seeking novel anti-tumor compounds with high efficiency and low toxicity from natural products can produce a new tumor treatment method. Matijin-Su [N-(N-benzoyl-L-phenylalanyl)-O-acetyl-L-phenylalanol, MTS] is a phenylalanine dipeptide monomer compound that is isolated from the Chinese ethnic medicine Matijin (Dichondra repens Forst.). Its derivatives exhibit various pharmacological activities, especially anti-tumor. Among them, the novel MTS derivative HXL131 has a significant inhibitory effect against prostate tumor growth and metastasis. This study is designed to investigate the effects of HXL131 on the growth and metastasis of human PCa cell lines PC3 and its molecular mechanism through in vitro experiments combined with proteomics, molecular docking, and gene silencing. The in vitro results showed that HXL131 concentration dependently inhibited PC3 cell proliferation, induced apoptosis, arrested cell cycle at the G2/M phase, and inhibited cell migration capacity. A proteomic analysis and a Western blot showed that HXL131 up-regulated the expression of proliferation, apoptosis, cell cycle, and migration-related proteins CYR61, TIMP1, SOD2, IL6, SERPINE2, DUSP1, TNFSF9, OSMR, TNFRSF10D, and TNFRSF12A. Molecular docking, a cellular thermal shift assay (CETSA), and gene silencing showed that HXL131 had a strong binding affinity with DUSP1 and TNFSF9, which are important target genes for inhibiting the growth and metastasis of PC3 cells. This study demonstrates that HXL131 exhibited excellent anti-prostate cancer activity and inhibited the growth and metastasis of prostate cancer cells by regulating the expression of DUSP1 and TNFSF9.

Angiogenesis-related lncRNAs index: A predictor for CESC prognosis, immunotherapy efficacy, and chemosensitivity

“…It has been shown that TNFSF9 can promote metastasis of pancreatic cancer through Wnt/Snail signaling and macrophage M2 polarization 30 . It has also been shown that by targeting TNFSF9 can inhibit the growth and metastasis of prostate cells 31 . However, unfortunately, there are no relevant experiments in cervical cancer that can draw similar conclusions as the previous ones.…”

ZNF643/ZFP69B Exerts Oncogenic Properties and Associates with Cell Adhesion and Immune Processes

“…Besides the influence on immune signaling, our in vitro and sequencing experiments revealed that ZNF643 is involved in cell migration, invasion, and adhesion. While TNFSF9 was previously demonstrated to play a role in these processes [34,35], SYNE3, another gene regulated by ZNF643, is implicated in migratory activities [36,37]. SYNE3 is a part of the linker of the nucleoskeleton and cytoskeleton (LINC) complex, which is crucial for the organization and dynamics of the perinuclear cytoskeleton [37,38].…”