AaTs-1: A Tetrapeptide from Androctonus australis Scorpion Venom, Inhibiting U87 Glioblastoma Cells Proliferation by p53 and FPRL-1 Up-Regulations

被引:12
作者
Aissaoui-Zid, Dorra [1 ]
Saada, Mohamed-Chiheb [1 ]
Moslah, Wassim [1 ]
Potier-Cartereau, Marie [2 ]
Lemettre, Aude [2 ]
Othman, Houcemeddine [1 ,3 ]
Gaysinski, Marc [4 ]
Abdelkafi-Koubaa, Zaineb [1 ]
Souid, Soumaya [5 ,6 ]
Marrakchi, Naziha [1 ]
Vandier, Christophe [2 ]
Essafi-Benkhadir, Khadija [5 ]
Srairi-Abid, Najet [1 ]
机构
[1] Univ Tunis El Manar, Inst Pasteur Tunis, Lab Biomolecules Venoms & Theranost Applicat, LR20IPT01, Tunis 1002, Tunisia
[2] Univ Tours, INSERM, N2C UMR 1069, F-37032 Tours, France
[3] Univ Witwatersrand, Sydney Brenner Inst Mol Biosci, Fac Hlth Sci, ZA-2041 Johannesburg, South Africa
[4] Univ Nice Sophia Antipolis, Chem Technol Platform NMR Dept, Fac Sci, Parc Valrose, F-06108 Nice, France
[5] Univ Tunis El Manar, Inst Pasteur Tunis, Lab Mol Epidemiol & Expt Pathol Appl Infect Dis, LR16IPT04, Tunis 1002, Tunisia
[6] Univ Louisiana, Sch Basic Pharmaceut & Toxicol Sci, Coll Pharm, Monroe, LA 71201 USA
关键词
glioblastoma; scorpion venom; AaTs-1; antiproliferative effect; FPRL-1; receptor; antagonist; FORMYL PEPTIDE RECEPTORS; CHEMICAL-SYNTHESIS; GLIOMA-CELLS; TEMOZOLOMIDE; PROTEIN; PURIFICATION; INVASION; ACTIVATION; CHLOROTOXIN; RESISTANCE;
D O I
10.3390/molecules26247610
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glioblastoma is an aggressive cancer, against which medical professionals are still quite helpless, due to its resistance to current treatments. Scorpion toxins have been proposed as a promising alternative for the development of effective targeted glioblastoma therapy and diagnostic. However, the exploitation of the long peptides could present disadvantages. In this work, we identified and synthetized AaTs-1, the first tetrapeptide from Androctonus australis scorpion venom (Aa), which exhibited an antiproliferative effect specifically against human glioblastoma cells. Both the native and synthetic AaTs-1 were endowed with the same inhibiting effect on the proliferation of U87 cells with an IC50 of 0.56 mM. Interestingly, AaTs-1 was about two times more active than the anti-glioblastoma conventional chemotherapeutic drug, temozolomide (TMZ), and enhanced its efficacy on U87 cells. AaTs-1 showed a significant similarity with the synthetic peptide WKYMVm, an agonist of a G-coupled formyl-peptide receptor, FPRL-1, known to be involved in the proliferation of glioma cells. Interestingly, the tetrapeptide triggered the dephosphorylation of ERK, p38, and JNK kinases. It also enhanced the expression of p53 and FPRL-1, likely leading to the inhibition of the store operated calcium entry. Overall, our work uncovered AaTs-1 as a first natural potential FPRL-1 antagonist, which could be proposed as a promising target to develop new generation of innovative molecules used alone or in combination with TMZ to improve glioblastoma treatment response. Its chemical synthesis in non-limiting quantity represents a valuable advantage to design and develop low-cost active analogues to treat glioblastoma cancer.
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页数:23
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