Nizam Esra, Erin Nuray
Department of Medical Pharmacology, Akdeniz University, Faculty of Medicine, Antalya, Turkey.
Department of Medical Pharmacology, Akdeniz University, Faculty of Medicine, Antalya, Turkey.
Biomed Pharmacother. 2018 Dec;108:263-270. doi: 10.1016/j.biopha.2018.09.013. Epub 2018 Sep 14.
The biological action of Substance P (SP) is mediated mainly by NK-1 receptors (NK1R) followed by NK2 receptors (NK2R). Aberrant expression of NK1R and NK2R has been identified in various carcinomas. The role of Substance P and its receptors, especially NK2R in cancer progression is not entirely known and there are conflicting results in the literature demonstrating the need for further investigation. In the current study, we examined the effects of SP and antagonists selective for the NK1R and NK2R in breast carcinoma cells metastasize to vital organs.
The effects of highly potent and selective non-peptide mouse NK1R and NK2R antagonists RP 67,580 and GR 159897, respectively, as well as SP and SP methyl ester, on both metastatic (4THM, 4TBM, 4TLM, 4T1) and non-metastatic (67NR) breast cancer cells were determined.
NK1R and NK2R were over expressed in metastatic breast cells compared to non-metastatic cells. The NK1R antagonist at a 30 μM dose inhibited cell growth and induced cell death in metastatic cells while enhancing phosphorylation of Akt, the latter response not observed in the non-metastatic 67NR cells. Blocking the action of SP at the NK2R (30 μM antagonist) suppressed cellular proliferation in all the cell lines examined, with a response less prominent than that of the NK1R antagonist. Differently, the NK2R antagonist increased phosphorylation of p38 and enhanced MIP-2 secretion. SP and the SP methyl ester neither altered cell proliferation nor the effects of NK1R and NK2R antagonists in the metastatic cell lines.
Increased sensitivity of metastatic breast carcinoma cells to NK1R and NK2R antagonists suggest potential therapeutic value of antagonists in metastatic disease. NK1R and NK2R in metastatic breast carcinoma cells react differently to agonists and antagonists. These findings together with previously published data demonstrate that differential consequences of receptor antagonists and SP may inhibit breast cancer growth and metastasis.
P物质（SP）的生物学作用主要由NK-1受体（NK1R）介导，其次是NK-2受体（NK2R）。NK1R和NK2R在各种癌症中均有异常表达。P物质及其受体，尤其是NK2R在癌症进展中的作用尚不完全清楚，文献中的结果相互矛盾，表明有必要进一步研究。在本研究中，我们检测了SP以及对NK1R和NK2R有选择性的拮抗剂对转移至重要器官的乳腺癌细胞的影响。
分别检测了高效且选择性的非肽类小鼠NK1R拮抗剂RP 67,580和NK2R拮抗剂GR 159897，以及SP和SP甲酯对转移性（4THM、4TBM、4TLM、4T1）和非转移性（67NR）乳腺癌细胞的作用。
与非转移性细胞相比，转移性乳腺癌细胞中NK1R和NK2R表达上调。30 μM剂量的NK1R拮抗剂可抑制转移性细胞的生长并诱导其死亡，同时增强Akt的磷酸化，在非转移性67NR细胞中未观察到后一种反应。在NK2R处阻断SP的作用（30 μM拮抗剂）可抑制所有检测细胞系中的细胞增殖，其反应不如NK1R拮抗剂明显。不同的是，NK2R拮抗剂增加了p38的磷酸化并增强了MIP-2的分泌。SP和SP甲酯在转移性细胞系中既未改变细胞增殖，也未改变NK1R和NK2R拮抗剂的作用。
转移性乳腺癌细胞对NK1R和NK2R拮抗剂的敏感性增加表明拮抗剂在转移性疾病中具有潜在的治疗价值。转移性乳腺癌细胞中的NK1R和NK2R对激动剂和拮抗剂的反应不同。这些发现与先前发表的数据共同表明，受体拮抗剂和SP的不同作用可能会抑制乳腺癌的生长和转移。
