Peimine inhibits the growth and motility of prostate cancer cells and induces apoptosis by disruption of intracellular calcium homeostasis through Ca2+ /CaMKII/JNK pathway

Prostate Cancer (PC) is one of the most common malignant tumors in man. Peimine (PM) is a bioactive substance isolated from Fritillaria. Previous studies have shown that PM could inhibit the occurrence of a variety of cancers. However, the roles of PM in PC and its related mechanism have not been elucidated. Calcium (CA²⁺ ) is an important intracellular messenger involved in a variety of cell processes. In this study, we found that the appropriate doses of PM (2.5, 5, and 10 μM) significantly inhibited the growth of PC cells (DU-145, LNCap, and PC-3), but has no significant effect on normal prostate cells (RWPE-1). In addition, PM treatment inhibited the invasion and migration of PC-3 cells and blocked the epithelial-mesenchymal transition process. These effects were exhibited a dose-dependent manner. Furthermore, the current results also showed that PM treatment significantly increased the CA²⁺ concentration, the increased CA²⁺ promoted the phosphorylation of CA²⁺ /calmodulin-dependent protein kinase II (CaMKII) and c-Jun N-terminal kinase (JNK), further inhibited the growth and invasion of PC-3 cells, and induced its Apoptosis. CA²⁺ chelator BAPTA-AM (1 μM) could counteract the increase of intracellular CA²⁺ concentration. Similarly, JNK pathway inhibitor SP600125 (10 μM) also inhibited cell growth and invasion and induced Apoptosis. In addition, experiments in nude mice showed that PM inhibited tumor formation through CA²⁺ /CaMKII/JNK signaling pathway. In conclusion, our results show that PM inhibits the growth and motility of prostate Cancer cells and induces Apoptosis by disruption of intracellular calcium homeostasis through CA²⁺ /CaMKII/JNK pathway.

Ca2+/CaMKII; JNK; calcium; endoplasmic reticulum stress; peimine; prostate cancer.