J. Pharm. Pharmacogn. Res., vol. 13, no. 1, pp. 341-355, Jan-Feb 2025.
DOI: https://doi.org/10.56499/jppres24.2085_13.1.341Original Article
Bioinformatic investigation of Lytechinus variegatus coelomic fluid peptides as multiple oncogenic proteins inhibitors of colorectal cancer
[Investigación bioinformática de péptidos del líquido celómico de Lytechinus variegatus como inhibidores de múltiples proteínas oncogénicas del cáncer colorrectal]
Rauza S. Rita1*, Kevin N. Cuandra2, Salsabila P. Khairani3, Rizky E. Putera4, Vella Amalia2, Alifya R. Shofiy5, Dhyani P. Wahyudi5, Ahmad R. Yustian2, Dinda P. Nabila6, Malya C. S. Maharani5, Andi A. D. Kahar7
1Department of Biochemistry, Faculty of Medicine, Universitas Andalas, Padang, Indonesia.
2Department of Medicine, Faculty of Medicine, Universitas Andalas, Padang, Indonesia.
3Department of Biomedical Science, Faculty of Medicine, Universitas Andalas, Padang, Indonesia.
4Department of Medicine, Faculty of Medicine, Universitas Sebelas Maret, Surakarta, Indonesia.
5Department of Medicine, Faculty of Medicine, Universitas Pembangunan Nasional "Veteran", Jakarta, Indonesia.
6Department of Pharmacy, Faculty of Pharmacy, Universitas Andalas, Padang, Indonesia.
7Departement of Physics, Faculty of Mathematics and Natural Science, Universitas Brawijaya, Malang, Indonesia.
*E-mail: rauzasukmarita@med.unand.ac.id
Abstract
Context: Colorectal cancer (CRC) remains a significant global health challenge despite advances in treatment modalities. The coelomic fluid of Lytechinus variegatus emerges as a rich source of bioactive peptides with the potential as a new therapeutic anticancer agent.
Aims: To analyze the toxicity, allergenicity, and potential of L. variegatus coelomic fluid peptides as multitarget inhibitor agents of CRC cancer cells through an in silico study.
Methods: Ten peptides from L. variegatus coelomic fluid were processed using UCSF Chimera software to model the three-dimensional structure. ToxinPred and AllerTop web servers were used to analyze the toxicity and allergenicity of peptides, respectively. The 3D structures of EGFR, AKT1, GSK3B, VEGFR2, and JAK3 were retrieved from the PDBJ database. MOE Software was used to perform molecular docking.
Results: Peptide 4 binds to the ATP binding pocket of GSK3B protein with the strongest binding affinity value (-8,68 kcal/mol). The docking results between EGFR and peptides showed that peptide 10 binds to the ATP binding pocket with the lowest binding affinity (-9.52 kcal/mol). Peptide 2 binds to the ATP binding pocket of AKT1 with the lowest binding affinity value (-9.16 kcal/mol). Peptide 3 has the lowest binding affinity value of the JAK3 ATP binding pocket (-8,67 kcal/mol). Peptide 7 binds to the ATP binding pocket of VEGFR2 with the strongest binding affinity (-9,67 kcal/mol).
Conclusions: The L. variegatus peptides have the potential as multitarget anti-CRC agents by inhibiting the activity of GSK3B, EGFR, AKT1, JAK3, and VEGFR2 proteins through the ATP competitive inhibitor action based on in silico study.
Keywords: anticancer; colorectal cancer; Lytechinus variegatus; molecular docking.
Resumen
Contexto: El cáncer colorrectal (CCR) sigue siendo un importante desafío para la salud mundial a pesar de los avances en las modalidades de tratamiento. El líquido celómico de Lytechinus variegatus surge como una rica fuente de péptidos bioactivos con potencial como nuevo agente terapéutico contra el cáncer.
Objetivos: Analizar la toxicidad, la alergenicidad y el potencial de los péptidos del líquido celómico de L. variegatus como agentes inhibidores multidiana de las células cancerosas del CCR a través de un estudio in silico.
Métodos: Se procesaron diez péptidos del líquido celómico de L. variegatus utilizando el software UCSF Chimera para modelar la estructura tridimensional. Se utilizaron los servidores web ToxinPred y AllerTop para analizar la toxicidad y la alergenicidad de los péptidos, respectivamente. Las estructuras 3D de EGFR, AKT1, GSK3B, VEGFR2 y JAK3 se recuperaron de la base de datos PDBJ. Se utilizó el software MOE para realizar el acoplamiento molecular.
Resultados: El péptido 4 se une al bolsillo de unión de ATP de la proteína GSK3B con el valor de afinidad de unión más fuerte (-8,68 kcal/mol). Los resultados del acoplamiento entre EGFR y péptidos mostraron que el péptido 10 se une al bolsillo de unión de ATP con la afinidad de unión más baja (-9,52 kcal/mol). El péptido 2 se une al bolsillo de unión de ATP de AKT1 con el valor de afinidad de unión más bajo (-9,16 kcal/mol). El péptido 3 tiene el valor de afinidad de unión más bajo del bolsillo de unión de ATP de JAK3 (-8,67 kcal/mol). El péptido 7 se une al bolsillo de unión de ATP de VEGFR2 con la afinidad de unión más fuerte (-9,67 kcal/mol).
Conclusiones: Los péptidos de L. variegatus tienen potencial como agentes anti-CRC multidiana al inhibir la actividad de las proteínas GSK3B, EGFR, AKT1, JAK3 y VEGFR2 a través de la acción inhibidora competitiva de ATP basada en un estudio in silico.
Palabras Clave: acoplamiento molecular; anticancerígeno; cáncer colorrectal; Lytechinus variegatus.
Citation Format: Rita SR, Cuandra KN, Khairani SP, Putera RE, Amalia V, Shofiy AR, Wahyudi DP, Yustian AR, Nabila DP, Maharani MCS, Kahar AAD (2025) Bioinformatic investigation of Lytechinus variegatus coelomic fluid peptides as multiple oncogenic proteins inhibitors of colorectal cancer. J Pharm Pharmacogn Res 13(1): 341–355. https://doi.org/10.56499/jppres24.2085_13.1.341
References
Alhazzani K, Venkatesan T, Natarajan U, Algahtani M, Alaseem A, Alobid S, Rathinavel A (2022) Evaluation of antitumor effects of VEGFR-2 inhibitor F16 in a colorectal xenograft model. Biotechnol Lett 44(5–6): 787–801. https://doi.org/10.1007/S10529-022-03243-0
Baammi S, El Allali A, Daoud R (2023) Unleashing Nature’s potential: a computational approach to discovering novel VEGFR-2 inhibitors from African natural compound using virtual screening, ADMET analysis, molecular dynamics, and MMPBSA calculations. Front Mol Biosci 10: 1227643. https://doi.org/10.3389/FMOLB.2023.1227643
Boroughs LK, Deberardinis RJ (2015) Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol 17(4): 351–359. https://doi.org/10.1038/NCB3124
Chang CH, Lee CY, Lu CC, Tsai FJ, Hsu YM, Tsao JW, Juan YN, Chiu HY, Yang JS, Wang CC (2017) Resveratrol-induced autophagy and apoptosis in cisplatin-resistant human oral cancer CAR cells: A key role of AMPK and Akt/mTOR signaling. Int J Oncol 50(3): 873–882. https://doi.org/10.3892/IJO.2017.3866
Codenotti S, Zizioli D, Mignani L, Rezzola S, Tabellini G, Parolini S, Giacomini, A, Asperti M, Poli M, Mandracchia D, Vezzoli M, Bernardi S, Russo D, Mitola S, Monti E, Triggiani L, Tomasini D, Gastaldello S, Cassandri M, Fanzani A (2022) Hyperactive Akt1 signaling increases tumor progression and DNA repair in embryonal rhabdomyosarcoma RD line and confers susceptibility to glycolysis and mevalonate pathway inhibitors. Cells 11(18): 2859. https://doi.org/10.3390/CELLS11182859
Cormier KW, Woodgett JR, Beaulieu JM, Eldar-Finkelman H (2017) Recent advances in understanding the cellular roles of GSK-3. F1000Res 6: 167. https://doi.org/10.12688/f1000research.10557.1
Dewi FRP, Domoto T, Hazawa M, Kobayashi A, Douwaki T, Minamoto T, Wong RW (2018) Colorectal cancer cells require glycogen synthase kinase-3β for sustaining mitosis via translocated promoter region (TPR)-dynein interaction. Oncotarget 9(17): 13337–13352. https://doi.org/10.18632/ONCOTARGET.24344
Domoto T, Uehara M, Bolidong D, Minamoto T (2020) Glycogen synthase kinase 3β in cancer biology and treatment. Cells 9(6):1388. https://doi.org/10.3390/CELLS9061388
Foersch S, Sperka T, Lindner C, Taut A, Rudolph KL, Breier G, Boxberger F, Rau TT, Hartmann A, Stürzl M, Wittkopf N, Haep L, Wirtz S, Neurath MF, Waldner MJ (2015) VEGFR2 signaling prevents colorectal cancer cell senescence to promote tumorigenesis in mice with colitis. Gastroenterology 149(1): 177-189e10. https://doi.org/10.1053/j.gastro.2015.03.016
Freund E, Liedtke KR, Miebach L, Wende K, Heidecke A, Kaushik NK, Choi EH, Partecke LI, Bekeschus S (2020) Identification of two kinase inhibitors with synergistic toxicity with low-dose hydrogen peroxide in colorectal cancer cells in vitro. Cancers 12(1): 122. https://doi.org/10.3390/CANCERS12010122
Gong B, Li Z, Xiao W, Li G, Ding S, Meng A, Jia S (2019) Sec14l3 potentiates VEGFR2 signaling to regulate zebrafish vasculogenesis. Nat Comm 10(1): 1606. https://doi.org/10.1038/s41467-019-09604-0
He Y, Sun MM, Zhang GG, Yang J, Chen KS, Xu WW, Li B (2021) Targeting PI3K/Akt signal transduction for cancer therapy. Sig Transduct Target Ther 6(1): 425. https://doi.org/10.1038/S41392-021-00828-5
Janani B, Vijayakumar M, Priya K, Kim JH, Prabakaran DS, Shahid M, Al-Ghamdi S, Alsaidan M, Othman BN, Hassan AM, Ramesh T (2022) EGFR-based targeted therapy for colorectal cancer—Promises and challenges. Vaccines 10(4): 499. https://doi.org/10.3390/VACCINES10040499
Kano A, Iwasaki T, Shindo M (2019) Bongkrekic acid facilitates glycolysis in cultured cells and induces cell death under low glucose conditions. Biochem Biophys Rep 20: 100683. https://doi.org/10.1016/J.BBREP.2019.100683
Khalifa SAM, Elias N, Farag MA, Chen L, Saeed A, Hegazy MEF, Moustafa MS, El-Wahed AA, Al-Mousawi SM, Musharraf SG, Chang FR, Iwasaki A, Suenaga K, Alajlani M, Göransson U, El-Seedi HR (2019) Marine natural products: A source of novel anticancer drugs. Mar Drugs 17(9): 491. https://doi.org/10.3390/MD17090491
Krzyszczyk P, Acevedo A, Davidoff EJ, Timmins LM, Marrero-Berrios I, Patel M, White C, Lowe C, Sherba JJ, Hartmanshenn C, O’Neill KM, Balter ML, Fritz ZR, Androulakis IP, Schloss RS, Yarmush ML (2018) The growing role of precision and personalized medicine for cancer treatment. Technology 6(3–4): 79–100. https://doi.org/10.1142/S2339547818300020
Liao Z, Li F, Zhang C, Zhu L, Shi Y, Zhao G, Bai X, Hassan S, Liu X, Li T, Xing P, Zhao J, Zhang J, Xing R, Teng S, Yang Y, Chen K, Yang J (2019) Phase II trial of VEGFR2 inhibitor apatinib for metastatic sarcoma: focus on efficacy and safety. Exp Mol Med 51: 1–11. https://doi.org/10.1038/S12276-019-0221-7
Liu K, Ren T, Huang Y, Sun K, Bao X, Wang S, Zheng B, Guo W (2017) Apatinib promotes autophagy and apoptosis through VEGFR2/STAT3/BCL-2 signaling in osteosarcoma. Cell Death Dis 8(8): e3015. https://doi.org/10.1038/cddis.2017.422
Manning BD, Toker A (2017) AKT/PKB signaling: Navigating the network. Cell 169(3): 381–405. https://doi.org/10.1016/J.CELL.2017.04.001
Meng L, Ding L, Yu Y, Li W (2020) JAK3 and TYK2 serve as prognostic biomarkers and are associated with immune infiltration in stomach adenocarcinoma. BioMed Res Int 2020: 7973568. https://doi.org/10.1155/2020/7973568
Nacion AJD, Park YY, Kim NK (2018) Contemporary management of locally advanced rectal cancer: Resolving issues, controversies and shifting paradigms. Chin J Cancer 30(1): 131–146. https://doi.org/10.21147/J.ISSN.1000-9604.2018.01.14
Ni H, Guo M, Zhang X, Jiang L, Tan S, Yuan J, Cui H. L, Min Y, Zhang J, Schlisio S, Ma C, Liao W, Nister M, Chen C, Li S, Li N (2021) VEGFR2 inhibition hampers breast cancer cell proliferation via enhanced mitochondrial biogenesis. Cancer Biol Med 18(1): 139–154. https://doi.org/10.20892/J.ISSN.2095-3941.2020.0151
Oronsky B, Reid T, Larson C, Knox SJ (2020) Locally advanced rectal cancer: The past, present, and future. Sem Oncol 47(1): 85–92. https://doi.org/10.1053/J.SEMINONCOL.2020.02.001
Pabla B, Bissonnette M, Konda VJ (2015) Colon cancer and the epidermal growth factor receptor: Current treatment paradigms, the importance of diet, and the role of chemoprevention. World J Clin Oncol 6(5): 133–141. https://doi.org/10.5306/WJCO.V6.I5.133
Pan X, Xu J, Jia X (2020) Research progress evaluating the function and mechanism of anti-tumor peptides. Cancer Manag Res12: 397–409. https://doi.org/10.2147/CMAR.S232708
Sciani JM, Emerenciano AK, Cunha da Silva JR, Pimenta DC (2016) Initial peptidomics profiling of Brazilian sea urchins: Arbacia lixula, Lytechinus variegatus, and Echinometra lucunter. J Venom Anim Toxins Incl Trop Dis 22: 17. https://doi.org/10.1186/s40409-016-0071-x
Siegel RL, Miller KD, Wagle NS, Jemal A (2023) Cancer statistics, 2023. CA Cancer J Clin. 73(1): 17–48. https://doi.org/10.3322/caac.21763
Vidri RJ, Fitzgerald TL (2020) GSK-3: An important kinase in colon and pancreatic cancers. Biochim Biophys Acta Mol Cell Res 1867(4): 118626. https://doi.org/10.1016/J.BBAMCR.2019.118626
Wang X, Bove AM, Simone G, Ma B (2020) Molecular bases of VEGFR-2-mediated physiological function and pathological role. Front Cell and Dev Biol 8: 599281. https://doi.org/10.3389/FCELL.2020.599281
Xiong Z, Graves DB (2017) A novel cupping-assisted plasma treatment for skin disinfection. J Phys D: Appl Phys 50(5): 05LT01. https://doi.org/10.1088/1361-6463/50/5/05LT01
Zhang N, Tian YN, Zhou LN, Li MZ, Chen HD, Song SS, Huan XJ, Bao X, Bin Zhang A, Miao ZH, He JX (2021) Glycogen synthase kinase 3β inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer. Cell Death Dis 12(2): 183. https://doi.org/10.1038/s41419-021-03475-4
Zhong M, Li N, Qiu X, Ye Y, Chen H, Hua J, Yin P, Zhuang G (2020) TIPE regulates VEGFR2 expression and promotes angiogenesis in colorectal cancer. Int J Biol Sci 16(2): 272–283. https://doi.org/10.7150/IJBS.37906
Zhou J, Ji Q, Li Q (2021) Resistance to anti-EGFR therapies in metastatic colorectal cancer: Underlying mechanisms and reversal strategies. J Exp Clin Cancer Res 40: 328. https://doi.org/10.1186/S13046-021-02130-2
© 2025 Journal of Pharmacy & Pharmacognosy Research