SP/NK‐1R promotes gallbladder cancer cell proliferation and migration

Abstract

Aberrant substance P/neurokinin‐1 receptor (SP/NK‐1R) system activation plays a critical role in various disorders, however, little is known about the expression and the detailed molecular mechanism of the SP and NK‐1R in gallbladder cancer (GBC). In this study, we firstly analyzed the expression and clinical significance of them in patients with GBC. Then, cellular assays were performed to clarify their biological role in GBC cells. Moreover, we investigated the molecular mechanisms regulated by SP/NK‐1R. Meanwhile, mice xenografted with human GBC cells were analyzed regarding the effects of SP/NK1R complex in vivo. Finally, patient samples were utilized to investigate the effect of SP/NK‐1R. The results showed that SP and NK‐1R were highly expressed in GBC. We found that SP strongly induced GBC cell proliferation, clone formation, migration and invasion, whereas antagonizing NK‐1R resulted in the opposite effects. Moreover, SP significantly enhanced the expression of NF‐κB p65 and the tumor‐associated cytokines, while, Akt inhibitor could reverse these effects. Further studies indicated that decreasing activation of NF‐κB or Akt diminished GBC cell proliferation and migration. In consistent with results, immunohistochemical staining showed high levels of Akt, NF‐κB and cytokines in tumor tissues. Most importantly, the similar conclusion was obtained in xenograft mouse model. Our findings demonstrate that NK‐1R, after binding with the endogenous agonist SP, could induce GBC cell migration and spreading via modulation of Akt/NF‐κB pathway.

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“…In tumor cells, SP through the NK-1R promotes an anti-apoptotic effect as well as proliferation, migration, invasion and metastasis ( Figure 1) [13,25,27,30,36,37]. Cancer cells express both SP and the NK-1R, and it seems that the undecapeptide is involved in an autocrine mechanism that promotes mitogenesis in tumor cells [13,21,28,[38][39][40][41][42][43][44].…”

“…It is also important to note that the SP/NK-1R system is involved in the migration of cancer cells ( Figure 1) [36]. This mechanism is mediated by the Akt/NF-κB pathway: the undecapeptide increases tumor-associated cytokines and NF-κB p65 expression and decreases cancer cell proliferation/migration when a reduced activation of Akt/NF-κB occurs [36]. The SP/NK-1R system also controls membrane blebbing, a mechanism related to cell migration and spreading ( Figure 1) [27,36,57,58].…”

“…It has been reported that the truncated isoform mediates tumor cell malignancy, increases the growth of these cells and promotes the synthesis of cytokines which exert growth-promoting effects (activates NF-κB that up-regulates the truncated isoform but slightly increases the full-length form), whereas the full-length isoform induces slow cancer cell growth [94][95][96]. By immunohistochemistry, a high level of NF-κB and cytokines has been reported in tumor tissues [36] and it has been shown that an increase in the expression of the NK-1R was observed after the activation of NF-κB by SP; thus, SP increases the expression of its natural ligand, the NK-1R [97].…”

“…This mechanism is mediated by the Akt/NF-κB pathway: the undecapeptide increases tumor-associated cytokines and NF-κB p65 expression and decreases cancer cell proliferation/migration when a reduced activation of Akt/NF-κB occurs [ 36 ]. The SP/NK-1R system also controls membrane blebbing, a mechanism related to cell migration and spreading ( Figure 1 ) [ 27 , 36 , 57 , 58 ]. Moreover, SP favors the expression of matrix metalloproteinases (degradative enzymes) by enhancing the activation of several signaling pathways (Akt, JNK, ERK1/2) and promoting cancer cell migration, invasion and metastasis [ 59 , 60 ], processes that are inhibited by NK-1R antagonists [ 36 ].…”

The Neurokinin-1 Receptor Antagonist Aprepitant: An Intelligent Bullet against Cancer?

“…SP accelerates the migration of esophageal squamous cell carcinoma (in which the NK-1R is overexpressed) and enhances the expression of factors involved in angiogenesis via the overexpression of vascular endothelial growth factor receptor 1 and vascular endothelial growth factor A [56]. It has been reported that by reducing the activation of Akt or NF-κB, the migration of cancer cells was attenuated [50]. It is also known that the expression of the full-length isoform of the NK-1R reduced metastasis, whereas the activation of the truncated form increased it [57]; that SP promoted the migration of cancer cells by modulating the level of intracellular Ca ++ [58]; and that in metastatic tumors, an increase in SP/NK-1R staining occurred [30].…”