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

Author:

Dong Yang123,Hao Lin123,Shi Zhen-duo12,Fang Kun4,Yu Hui5,Zang Guang-hui12,Fan Tao12,Han Cong-hui123ORCID

Affiliation:

1. Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu Province, China

2. Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu Province, China

3. Medical College of Soochow University, Soochow, Jiangsu Province, China

4. Department of Nephrology, The Third Affiliated Hospital of Shandong First Medical University, Jinan, Shandong Province, China

5. Department of Urology, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong Province, China

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.

Funder

National Natural Science Foundation of China

Publisher

Hindawi Limited

Subject

Oncology

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