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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 2/2020

Open Access 01-04-2020 | Breast Cancer | Preclinical study

pHLIP(Var7)-P1AP suppresses tumor cell proliferation in MDA-MB-231 triple-negative breast cancer by targeting protease activated receptor 1

Authors: MingMing Yu, YueHua Chen, ZhenGuang Wang, XiaoDong Ding

Published in: Breast Cancer Research and Treatment | Issue 2/2020

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Abstract

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.
Literature
1.
Foulkes WD, Smith IE, Reis-Filho JS (2010) Triple-negative breast cancer. N Engl J Med 363(20):1938–1948CrossRef
2.
Yang E, Boire A, Agarwal A, Nguyen N, O'Callaghan K, Tu P et al (2009) Blockade of PAR1 signaling with cell-penetrating pepducins inhibits Akt survival pathways in breast cancer cells and suppresses tumor survival and metastasis. Cancer Res 69(15):6223–6231CrossRef
3.
Pathak AP, Gimi B, Glunde K, Ackerstaff E, Artemov D, Bhujwalla ZM (2004) Molecular and functional imaging of cancer: advances in MRI and MRS. Methods Enzymol 386:3–60PubMed
4.
Penet MF, Glunde K, Jacobs MA, Pathak AP, Bhujwalla ZM (2008) Molecular and functional MRI of the tumor microenvironment. J Nucl Med 49(5):687–690CrossRef
5.
Vāvere AL, Biddlecombe GB, Spees WM, Garbow JR, Wijesinghe D, Andreev OA et al (2009) A novel technology for the imaging of acidic prostate tumors by positron emission tomography. Cancer Res 69(10):4510–4516CrossRef
6.
Zhang P, Gruber A, Kasuda S, Kimmelstiel C, O'Callaghan K, Cox DH et al (2012) Suppression of arterial thrombosis without affecting hemostatic parameters with a cell-penetrating PAR1 pepducin. Circulation 126(1):83–91CrossRef
7.
Covic L, Kuliopulos A (2018) Protease-activated receptor 1 as therapeutic target in breast, lung, and ovarian cancer: pepducin approach. Int J Mol Sci 19(8):2237CrossRef
8.
Dimond P, Carlson K, Bouvier M, Gerard C, Xu L, Covic L et al (2011) G protein-coupled receptor modulation with pepducins: moving closer to the clinic. Ann N Y Acad Sci 1226:34–49CrossRef
9.
Fukumura D, Jain RK (2007) Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize. J Cell Biochem 101(4):937–949CrossRef
10.
Izumi H, Torigoe T, Ishiguchi H, Uramoto H, Yoshida Y, Tanabe M et al (2003) Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev 29(6):541–549CrossRef
11.
Cairns R, Papandreou I, Denko N (2006) Overcoming physiologic barriers to cancer treatment by molecularly targeting the tumor microenvironment. Mol Cancer Res 4(2):61–70CrossRef
12.
Hunt JF, Earnest TN, Bousché O, Kalghatgi K, Reilly K, Horváth C et al (1997) A biophysical study of integral membrane protein folding. Biochemistry 36(49):15156–15176CrossRef
13.
Reshetnyak YK, Segala M, Andreev OA, Engelman DM (2007) A monomeric membrane peptide that lives in three worlds: in solution, attached to, and inserted across lipid bilayers. Biophys J 93(7):2363–2372CrossRef
14.
Wijesinghe D, Engelman DM, Andreev OA, Reshetnyak YK (2011) Tuning a polar molecule for selective cytoplasmic delivery by a pH (low) insertion peptide. Biochemistry 50(47):10215–10222CrossRef
15.
Moshnikova A, Moshnikova V, Andreev OA, Reshetnyak YK (2013) Antiproliferative effect of pHLIP-amanitin. Biochemistry 52(7):1171–1178CrossRef
16.
Karabadzhak AG, An M, Yao L, Langenbacher R, Moshnikova A, Adochite RC et al (2014) pHLIP-FIRE, a cell insertion-triggered fluorescent probe for imaging tumors demonstrates targeted cargo delivery in vivo. ACS Chem Biol 9(11):2545–2553CrossRef
17.
Cheng CJ, Bahal R, Babar IA, Pincus Z, Barrera F, Liu C et al (2015) MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature 518(7537):107–110CrossRef
18.
Song Q, Chuan X, Chen B, He B, Zhang H, Dai W et al (2016) A smart tumor targeting peptide-drug conjugate, pHLIP-SS-DOX: synthesis and cellular uptake on MCF-7 and MCF-7/Adr cells. Drug Deliv 23(5):1734–1746PubMed
19.
Burns KE, Thevenin D (2015) Down-regulation of PAR1 activity with a pHLIP-based allosteric antagonist induces cancer cell death. Biochem J 472(3):287–295CrossRef
20.
Burns KE, Robinson MK, Thevenin D (2015) Inhibition of cancer cell proliferation and breast tumor targeting of pHLIP-monomethyl auristatin E conjugates. Mol Pharm 12(4):1250–1258CrossRef
21.
Burns KE, McCleerey TP, Thevenin D (2016) pH-selective cytotoxicity of pHLIP-antimicrobial peptide conjugates. Sci Rep 6:28465CrossRef
22.
Wyatt LC, Moshnikova A, Crawford T, Engelman DM, Andreev OA, Reshetnyak YK (2018) Peptides of pHLIP family for targeted intracellular and extracellular delivery of cargo molecules to tumors. Proc Natl Acad Sci USA 115(12):E2811–E2818CrossRef
Metadata
Title
pHLIP(Var7)-P1AP suppresses tumor cell proliferation in MDA-MB-231 triple-negative breast cancer by targeting protease activated receptor 1
Authors
MingMing Yu
YueHua Chen
ZhenGuang Wang
XiaoDong Ding
Publication date
01-04-2020
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 2/2020
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-020-05560-2

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