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

• Published in: International journal of biological macromolecules Vol. 189; pp. 142 - 150
• Main Authors: Le, Hien Thi Thu, Murugesan, Akshaya, Ramesh, Thiyagarajan, Yli-Harja, Olli, Konda Mani, Saravanan, Kandhavelu, Meenakshisundaram
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 31.10.2021
• Subjects: Apoptosis - drug effects; Cell Line, Tumor; Drug design; Glutathione - metabolism; Humans; Indoles - chemistry; Indoles - pharmacology; Indoline derivative; Male; Mitochondrial Membranes - drug effects; Mitochondrial Membranes - metabolism; Molecular Dynamics Simulation; Molecular simulation; Prostate cancer; Prostatic Neoplasms - pathology; Purinergic P2Y Receptor Agonists - pharmacology; Purinergic receptor; Receptors, Purinergic P2Y1 - chemistry; Receptors, Purinergic P2Y1 - metabolism; PBS; Molecular simulation; HIC; DMSO; P2Y1R; Indoline derivative; PCa; MMP; Purinergic receptor; GPCRs; Drug design; GSH; Prostate cancer
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2021.08.103

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 interaction 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 mitochondrial 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. •3D molecular model of P2Y1-HIC ligand complex•The P2Y1-HIC complex was simulated and analysed.•P2Y1-HIC interaction selectively induces apoptosis in prostate cancer cells.•HIC decreased mitochondrial membrane potential activity in PCa cells.•HIC reduced glutathione in PCa cells.