Solasonine Induces Apoptosis and Inhibits Proliferation of Bladder Cancer Cells by Suppressing NRP1 Expression

Abstract

Solasonine, a steroidal alkaloid extracted from Solanum nigrum L., has been found to exert inhibitory effect on cancers. However, the underlying anticancer mechanisms of solasonine, particularly in urinary bladder cancer (BC), remain unclear. In this study, we identified the potential targets and biological functions associated with solasonine activity using a bioinformatics approach. Ingenuity pathway analysis revealed that neuropilin-1 (NRP1) and other signaling pathways, such as PI3K/AKT and ERK/MAPK pathways, were potentially involved in the therapeutic effects of solasonine. The ability of solasonine in inducing apoptosis and inhibiting proliferation in BC cells was confirmed experimentally, and the inhibition of ERK/MAPK, P38/MAPK, and PI3K/AKT pathways was validated by Western blot. Mechanistically, solasonine suppressed the expression of NRP1 protein, but not that of mRNA. Further results of molecular docking and molecular dynamics simulation analysis indicated that solasonine could directly bind to the b1 domain of NRP1 protein with a reasonable and stable docking conformation. We previously found that targeting NRP1 is a potential antitumor strategy. Combined with these findings, it can be speculated that the binding of solasonine with NRP1 on the cell membrane could prevent the formation of NRP1/VEGFA/VEGFR2 and NRP1/EGFR complexes, resulting in the inhibition of downstream signaling, including ERK/MAPK, P38/MAPK, and PI3K/AKT pathways. Additionally, intracellular solasonine could inhibit the membrane localization of NRP1 and provoke its cytoplasmic retention, facilitating the degradation of NRP1 protein in the cytoplasm. The dual effects induced by the binding of solasonine to NRP1 extracellularly and intracellularly could account for the antiproliferative and proapoptotic effects of solasonine on BC.

Neuropilins as potential biomarkers in hepatocellular carcinoma: a systematic review of basic and clinical implications

“…12,15,17,26,[35][36][37][38][39][40][41][42][43][44][45][46][47][48][51][52][53][54] Similar findings were reported for other tumor types, describing TGF-β and other signaling pathways as potential targets of NRP regulation. [76][77][78][79] Additionally, invasion, migration and metastasis were also found to be strongly modulated by both NRPs in different solid tumor models, 24,80,81 supporting roles for NRP1 and NRP2 in mechanisms underlying tumor progression and spread. Nevertheless, while these findings highlight interesting function for NRPs in HCC tumor progression and invasion abilities, further studies are needed to identify the exact mechanisms and signaling pathways modulated by NRP1 and NRP2.…”

Tectoridin inhibits the growth of bladder cancer by regulating PI3K/MAPK pathway through RAB27B

“…49,50 These pathways are often overactivated in BC, and targeted therapies to inhibit their activation have been proposed. 51 Notably, TEC has been shown to ameliorate proliferation and inflammation in TNF-α-stimulated HFLS-RA cells by repressing the TLR4/NLRP3/NF-κB signaling pathway. 52 Previous studies have also indicated that RAB27B overexpression facilitates the activation of the PI3K/AKT/mTORC1 pathway and the ERK/MAPK pathway in HEK293 cells.…”

Multi-omics analysis reveals genomic, clinical and immunological features of SARS-CoV-2 virus target genes in pan-cancer

“…TMPRSS2, a key gene mediating the entry of SARS-CoV-2 into humans, is highly expressed in prostate cancer and its high expression could promote the development of prostate cancer (37)(38)(39)(40). NRP1, serving as a key factor of SARS-CoV-2 virus infection (41), could increase the susceptibility of cancer patients to SARS-CoV-2 virus and targeting (42), and its overexpression is associated with poor prognosis in bladder cancer cells and hepatocellular carcinoma, and inhibiting its expression could promote tumor cell apoptosis (43,44). In addition, the increased expression of SCARB1 could promote cell transformation towards malignancy of clear cell renal cell carcinoma leading to poor prognosis of patients (45), while the over-expression of AXL could accelerate EGFR mutation and promote the metastasis, invasion or drug resistance of tumors such as lung cancer (46), colorectal cancer (47), pancreatic cancer (48) and prostate tumor (49).…”