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

Abstract

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.

Identification of the Molecular Mechanisms of Peimine in the Treatment of Cough Using Computational Target Fishing

“…Calcium influx or activation of calcium-activated potassium channels may contribute to cough reflex sensitivity induced by IFN-γ or capsaicin [28,29]. In prostate cancer cells, peimine can inhibit cell growth and motility, and induce apoptosis by disruption of intracellular calcium homeostasis through the Ca 2+ /CaMKII/JNK pathway [30]. Therefore, peimine may exert effects through multiple targets and multiple pathways for cough relief.…”

Natural drug sources for respiratory diseases from Fritillaria: chemical and biological analyses

“…Plant-derived agents may became a potential resource with a vital role in antineoplastic treatment; the therapeutic properties of several species have been discovered in a variety of cancers or cancer cells, such as human promyelocytic leukemia cells (HL-60) [ 55 , 91 ], A549 cells [ 55 ], oral keratinocytes [ 92 ], ovarian and endometrial cancer cell lines [ 93 , 94 ], S180 sarcoma and Lewis lung carcinoma [ 88 , 95 ], HeLa cells [ 96 ], human colorectal carcinoma cells [ 97 ], glioblastoma (GBM) cells [ 98 ], non-small cell lung cancer (NSCLC) [ 99 ], and prostate cancer [ 100 ] (Fig. 8 ).…”

“…The antineoplastic effect is mainly performed by the proliferation inhibition of cancer cells. In recent years, several studies have been conducted to explore the potential mechanisms of anticancer activity using chemical components or extracts from Fritillaria herbs; These mechanisms include promotion of cell differentiation [ 91 ], induction of apoptosis and G 0 G 1 cell cycle arrest [ 95 ] through a caspase pathway [ 88 , 92 ], apoptosis induction without affecting the caspase-3 activity level [ 55 ], activation inhibition of NF-κB [ 93 , 99 ], downregulation of TGF-β/SMAD signaling pathways [ 94 ], inhibition of tumor angiogenesis [ 88 ], induction of cellular stress and activating several anti- and pro-survival pathways [ 96 ], induction of autophagic cell death via activating autophagy-related signaling pathway AMPK-mTOR-ULK by promoting SQSTM1 (P62) [ 97 , 98 ], and disruption of intracellular calcium homeostasis through Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and c-Jun N-terminal kinase (JNK) pathway [ 100 ]. Peimine, as a common component of 12 Fritillaria species, has showed reversal of the multidrug resistance of tumor cells in vitro and reversed tumor cells through in vitro multidrug resistance activity.…”

“…In addition, the toxicity assays revealed that imperialine treatments did not significantly disturb the blood cell counts in mice nor exert any significant damage to the main organs, indicating a robust systemic safety [ 99 ]. Peimine can generated inhibition performance of the growth and motility of prostate cancer cells and is interpreted as the disruption of intracellular calcium homeostasis through the Ca 2+ /CaMKII/JNK pathway [ 100 ].…”

Effect of Dickkopf-1 (Dkk-1) and SP600125, a JNK Inhibitor, on Wnt Signaling in Canine Prostate Cancer Growth and Bone Metastases

“…Moreover, JNK upregulation is associated with resistance to chemotherapeutic drugs [ 15 ]. SP600125, an anthrapyrazolone and a small-molecule inhibitor of the JNK catalytic activity, has been reported to reduce tumor cell growth and invasion and induce apoptosis [ 13 , 16 ].…”