蛋白酶激活受体1（PAR1）普遍存在于肿瘤细胞表面，其同源蛋白片段PAR1激活肽（P1AP）可以抑制肿瘤细胞PAR1→鸟苷酸结合蛋白的信号转导。酸性插入肽（pHLIP）可以靶向酸性肿瘤微环境，成为运输P1AP至肿瘤细胞进行治疗的极佳载体。
2020年2月7日，施普林格自然旗下《乳腺癌研究与治疗》在线发表中国青岛大学附属医院的研究报告，通过二硫键将pHLIP羧基末端（Var7）与P1AP氨基末端进行连接，形成pHLIP(Var7)-P1AP，探讨了其对三阴性乳腺癌的治疗效果和作用机制。
该研究首先测定人类三阴性乳腺癌胸膜转移细胞MDA-MB-231和人类正常乳腺上皮细胞PAR1表面的PAR1表达水平。随后，在不同酸碱度下，分析荧光标记pHLIP(Var7)-P1AP与MDA-MB-231细胞的结合能力。最后，在pH值为7.4和6.0的条件下，分析pHLIP(Var7)-P1AP对MDA-MB-231细胞增殖的影响。
结果发现，PAR1高表达于MDA-MB-231细胞表面。
在酸性环境（pH值为6.0和5.0）中，荧光标记pHLIP(Var7)-P1AP与MDA-MB-231细胞的结合能力较高，并且随着酸性增强而增加。
在酸性环境（pH值为6.0）中，pHLIP(Var7)-P1AP可以显著抑制MDA-MB-231细胞增殖。pHLIP(Var7)-P1AP浓度为0.5、1、2、4、8μg/mL时，细胞增殖抑制率分别为3.39%、5.27%、14.29%、22.14%、35.69%。
因此，该研究结果表明，PAR1高表达于三阴性乳腺癌细胞表面，pHLIP(Var7)-P1AP可以有效靶向酸性环境中的三阴性乳腺癌细胞，通过抑制PAR1→鸟苷酸结合蛋白的信号转导，抑制三阴性乳腺癌细胞的生长。
Breast Cancer Res Treat. 2020 Feb 7. [Epub ahead of print]
pHLIP(Var7)-P1AP suppresses tumor cell proliferation in MDA-MB-231 triple-negative breast cancer by targeting protease activated receptor 1.
Yu M, Chen Y, Wang Z, Ding X.
The Affiliated Hospital of Qingdao University, Qingdao, China.
PURPOSE: Protease-activated receptor 1 (PAR1) is a signaling protein ubiquitously present on the surface of tumor cells, and its homologous protein fragment, PAR1-activating peptide (P1AP), can inhibit protein signal transduction of PAR1/G in tumor cells. pH (Low) insertion peptide (pHLIP) can target the acidic tumor microenvironment (TME) and can be used as an excellent carrier to deliver P1AP to tumor cells for therapeutic purposes.
METHODS: PAR1 expression on the surface of MDA-MB-231 cells and human MCF10A mammary epithelial cells was observed. The binding between fluorescent-labeled pHLIP(Var7)-P1AP and MDA-MB-231 cells under different pH values was analyzed. The effect of pHLIP(Var7)-P1AP on the proliferation of MDA-MB-231 cells was analyzed under the conditions of pH 7.4 and 6.0.
RESULTS: PAR1 was highly expressed on the surface of MDA-MB-231 cells. In an acidic environment (pH 6.0 and 5.0), fluorescent-labeled pHLIP(Var7)-P1AP and MDA-MB-231 cells had a high binding ability, and the binding ability increased with the decrease in pH. In an acidic environment (pH 6.0), pHLIP(Var7)-P1AP significantly inhibited MDA-MB-231 cell proliferation. With 0.5 μg, 1 μg, 2 μg, 4 μg, and 8 μg of pHLIP(Var7)-P1AP, the cell proliferation inhibition rates were 3.39%, 5.27%, 14.29%, 22.14%, and 35.69%, respectively.
CONCLUSION: PAR1 was highly expressed on the surface of MDA-MB-231 cells. pHLIP(Var7)-P1AP can effectively target MDA-MB-231 cells in an acidic environment and inhibit the growth of MDA-MB-231 cells by inhibiting the signal transduction of PAR1/G protein.
KEYWORDS: pH (low) insertion peptides (pHLIP); Protease-activated receptor 1 (PAR1); Triple-negative breast cancer (TNBC); Cell proliferation
PMID: 32034579
DOI: 10.1007/s10549-020-05560-2
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