Molecular interaction of HIC, an agonist of P2Y1 receptor, and its role in prostate cancer apoptosis

被引:13
作者
Le, Hien Thi Thu [1 ]
Murugesan, Akshaya [1 ,2 ]
Ramesh, Thiyagarajan [3 ]
Yli-Harja, Olli [4 ,5 ]
Saravanan, Konda Mani [6 ]
Kandhavelu, Meenakshisundaram [1 ]
机构
[1] Tampere Univ, Fac Med & Hlth Technol, Mol Signaling Lab, POB 553, Tampere 33101, Finland
[2] Lady Doak Coll, Dept Biotechnol, Madurai 625002, Tamil Nadu, India
[3] Prince Sattam Bin Abdulaziz Univ, Coll Med, Dept Basic Med Sci, Al Kharj 11942, Saudi Arabia
[4] Tampere Univ, Fac Med & Hlth Technol, Computat Syst Biol Grp, POB 553, Tampere 33101, Finland
[5] Inst Syst Biol, 1441N 34th St, Seattle, WA 98103 USA
[6] Scigen Res & Innovat Pvt Ltd, Periyar Technol Business Incubator, Thanjavur 613403, Tamil Nadu, India
关键词
Purinergic receptor; Indoline derivative; Drug design; Molecular simulation; Prostate cancer; PROTEIN-COUPLED RECEPTORS; GPCR; GLUTATHIONE; GENERATION; PREDICTION; INHIBITORS; DOCKING; TARGETS; GLIDE; FOCUS;
D O I
10.1016/j.ijbiomac.2021.08.103
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
Prostate cancer is a heterogeneous, slow growing asymptomatic cancer that predominantly affects man. A purinergic G-protein coupled receptor, P2Y1R, is targeted for its therapeutic value since it plays a crucial role in many key molecular events of cancer progression and invasion. Our previous study demonstrated that indoline derivative, 1 ((1-(2-Hydroxy-5-nitrophenyl) (4-hydroxyphenyl) methyl)indoline-4-carbonitrile; HIC), stimulates prostate cancer cell (PCa) growth inhibition via P2Y1R. However, the mode of interaction of P2Y1R with HIC involved in this process remains unclear. Here, we have reported the molecular interactions of HIC with P2Y1R. Molecular dynamics simulation was performed that revealed the stable specific binding of the protein-ligand complex. In vitro analysis has shown increased apoptosis of PCa-cells, PC3, and DU145, upon specific interac-tion of P2Y1R-HIC. This was further validated using siRNA analysis that showed a higher percentage of apoptotic cells in PCa-cells transfected with P2Y-siRNA-MRS2365 than P2Y-siRNA-HIC treatment. Decreased mitochon-drial membrane potential (MMP) activity and reduced glutathione (GSH) level show their role in P2Y1R-HIC mediated apoptosis. These in silico and in vitro results confirmed that HIC could induce mitochondrial apoptotic signaling through the P2Y1R activation. Thus, HIC being a potential ligand upon interaction with P2Y1R might have therapeutic value for the treatment of prostate cancer.
引用
收藏
页码:142 / 150
页数:9
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