Introduction: Cancer has been always a serious global health problem. Only in 2012, 14.1 million new cases of cancers and 8.2 million deaths due to cancer have been reported (Ferlay et al. 2015). Environmentally induced or inherited genetic mutations leads to losing normal regulation of growth mechanism in cancerous cells and subsequently produce neoplasm or tumor. Three popular strategies for treatment of cancers are chemotherapy, surgery and radiation. Considering that chemotherapy drugs are not cell-specific treatments, they cause significant side effects. Besides, some cancer cells can be resistant to chemotherapy, so it seems necessary to find a cell-specific targeted therapy (Raguz et al. 2008). Recombinant Trombocidin-1 (rTC-1) is a therapeutic peptide isolated from human blood platelets and it has considerable homology to IL-8. It’s antimicrobial and antifungal features were shown previously (Yazdi et al. 2019; Shi et al. 2017) but its anticancer feature is still uncovered. IL-8 eliminates cancer cells by interaction with CXCR1 receptor which has positive correlation with different cancers (Waugh et al. 2008). In this study, we have proposed a likely pathway for anti-cancerous effect of rTC-1 by the simulation of anticancer pathway of IL-8 for rTC-1.
Methods: Based on the significant similarity of rTC-1 and IL-8 in case of coding sequence, its tertiary structure was predicted through homology modeling. Conformational stability of rTC-1 and CXCR11-38 were evaluated during 200ns and 20ns MD simulations, respectively in human’s physiological body condition (temperature and pressure). Docking analyzes was done for the interaction of CXCR-11-38 and the predicted model for rTC-1. Molecular dynamic simulations (MD) was performed for 200ns to assess the stability of rTC-1_CXCR11-38 complex.
Results: In case of conformational stability of rTC-1 and CXCR11-38, despite upward trend of root-mean-square deviation (RMSD) for α-carbons in approximately first 5 ns for both peptides, the RMSD was almost plateaued after 20 and 10 ns for rTC-1 and CXCR11-38, respectively. Docking and MD simulations results showed that rTC-1 and IL-8 share almost the same residues in interaction with CXCR11-38 receptor. It was shown that binding energies of rTC-1_CXCR11-38 (-17.8189 kcal/mol) and IL-8_CXCR11-38 (-18.5881 kcal/mol) complexes were almost the same. Besides, the stability of the rTC-1_CXCR11-38 complex was shown during 200ns MD simulations. Based on the known crucial residues of IL-8 in complex with CXCR11-38, similarly, residue number 8, 12, 17 in the N-loop and the residue 61 in the C-terminal helix of rTC-1 interact with CXCR11-38 receptor.
Conclusion: According to this in silico investigation, it is highly probable that rTC-1 mimic the anti-cancerous pathway of IL-8.
References
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136 (5): E359-386.
Raguz S, Yagüe E (2008) Resistance to chemotherapy: new treatments and novel insights into an old problem. Br J Cancer 99 (3): 387
Yazdi FT, Tanhaeian A, Azghandi M, Vasiee A, Alizadeh Behbahani B, Mortazavi SA, Roshanak S (2019) Heterologous expression of Thrombocidin-1 in Pichia pastoris: Evaluation of its antibacterial and antioxidant activity. Microb Pathog 127: 91-96.
Shi D (2017) Cancer Cell Surface Negative Charges: A Bio-Physical Manifestation of the Warburg Effect. Nano LIFE 7 (03n04): 1771001
Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14 (21): 6735-6741.