Wnt5a is a representative protein ligand that activates a beta catenin independent pathway in Wnt signaling in cancer progression and spread in the palmitoylated form. So that its synthesis is augmented through promotion of its gene transcription in the malignant cells. Cisplatin is an important chemotherapeutic drug used in treatment of different types of advanced cancer. However, its usage is limited due to severe dose-limiting side effects, due to the lack of targeting therapy of cisplatin. On the other hand, the cancer cells developed resistance from cisplatin that is solved partially by C-glycosylation of cisplatin. Through this review article, we strongly suggest that the Wnt5a protein can be used as drug delivery molecule for cisplatin to target the malignant cells. This can be performed through the following steps: Firstly: use of Wnt5a in the depalmitoylated form to avoid its effect on cancer progression with improvement of its binding efficacy by two suggested modifications: 1) Glycosylation with sialic acid-containing glycoside to increase the binding affinity with the sialic acid on the surface of the malignant cells; 2) GPI anchoring modification: This can be performed through the Serine 282 in the Wnt5a molecule. Secondly, binding of the C-glycosylated cisplatin molecule with the modified Wnt5a molecule through the C-glycosylation bond. Since one Wnt5a molecule contains four asparagine molecules, it can bind with four molecules of C-glycosylated cisplatin molecules, hence higher concentration of cisplatin will attack one malignant cell.
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Atta, W. O. and Azeiz, A. Z. A. (2021). Wnt5a Role in Cisplatin Effect and Selectivity Augmentation in Cancer Therapy. Open Access Library Journal, 8, e7564. doi: http://dx.doi.org/10.4236/oalib.1107564.
Garcia Sar, D., Montes-Bayon, M., Aguado Ortiz, L., Blanco-Gonzalez, E., Sierra, L.M. and Sanz-Medel, A. (2008) In Vivo Detection of DNA Adducts Induced by Cisplatin Using Capillary HPLC-ICP-MS and Their Correlation with Genotoxic Damage in Dorsophilia melanogaster. Analytical and Bioanalytical Chemistry, 390, 37-44. https://doi.org/10.1007/s00216-007-1634-z
Bahadir, A., Ceyhan, A., Öz Gergin, Ö., Yalçin, B., ülger, M., Özyazgan, T.M. and Yay, A. (2018) Protective Effects of Curcmin and Beta Carotene on Cisplatin-Induced Cardiotoxicity: A Experimental Rat Model. The Anatolian Journal of Cardiology, 19, 213-221. https://doi.org/10.14744/AnatolJCardiol.2018.53059
Tromp, R.A., Stella, S.G., Marco, Timmers, C., van Zutphen, S., van der Marel, G.A., Overkleeft, H.S., van Boom, J.H. and Reedijk, J. (2004) The Beta-Glucuronyl-Based Prodrug Strategy Allows for Its Application on Beta-Glucuronyl-Platinum Conjugates. Bioorganic & Medicinal Chemistry Letters, 14, 4273-4279. https://doi.org/10.1016/j.bmcl.2004.06.015
Deng, D., Xu, C., Sun, P., Wu, J., Yan, C., Hu, M. and Yan, N. (2014) Crystal Structure of the Human Glucose Transporter GLUT1. Nature, 510, 121-125.
https://doi.org/10.1038/nature13306
Amable, L. (2016) Cisplatin Resistance and Opportunities for Precision Medicine. Pharmacological Research, 106, 27-36. https://doi.org/10.1016/j.phrs.2016.01.001
Chen, S.J., Kuo, C.C., Pan, H.Y., Tsou, T.C., Yeh, S.C. and Chang, J.Y. (2015) Mechanistic Basis of a Combination D-Penicillamine and Platinum Drugs Synergistically Inhibits Tumor Growth in Oxaliplatin-Resistant Human Cervical Cancer Cells in Vitro and in Vivo. Biochemical Pharmacology, 95, 28-37.
https://doi.org/10.1016/j.bcp.2015.03.006
Chen, S.J., Kuo, C.C., Pan, H.Y., Tsou, T.C., Yeh, S.C. and Chang, J.Y. (2016) Desferal Regulates hCtr1 and Transferrin Receptor Expression through Sp1 and Exhibits Synergistic Cytotoxicity with Platinum Drugs in Oxaliplatin-Resistant Human Cervical Cancer Cells in Vitro and in Vivo. Oncotarget, 7, 49310-49321.
https://doi.org/10.18632/oncotarget.10336
Lai, Y.H., Kuo, C., Kuo, M.T. and Chen, H.H.W. (2018) Modulating Chemosensitivity of Tumors to Platinum-Based Antitumor Drugs by Transcriptional Regulation of Copper Homeostasis. International Journal of Molecular Sciences, 19, Article No. 1486. https://doi.org/10.3390/ijms19051486
Öhrvik, H., Logeman, B., Turk, B., Reinheckel, T. and Thiele, D.J. (2016) Cathepsin Protease controls Copper and Cisplatin Accumulation via Cleavage of the Ctr1 Metal-Binding Ectodomain. Journal of Biological Chemistry, 291, 13905-13916.
https://doi.org/10.1074/jbc.M116.731281
Lee, Y.Y., Choi, C.H., Do, I.G., Song, S.Y., Lee, W., Park, H.S., Song, T.J., Kim, M.K., Kim, T.J., Lee, J.W., et al. (2011) Prognostic Value of the Copper Transporters, CTR1 and CTR2, in Patients with Ovarian Carcinoma Receiving Platinum-Based Chemotherapy. Gynecologic Oncology, 122, 361-365.
https://doi.org/10.1016/j.ygyno.2011.04.025
Yoshida, H., Teramae, M., Yamauchi, M., Fukuda, T., Yasui, T., Sumi, T., Honda, K. and Ishiko, O. (2013) Association of Copper Transporter Expression with Platinum Resistance in Epithelial Ovarian Cancer. Anticancer Research, 33, 1409-1414.
Hinoshita, E., Uchiumi, T., Taguchi, K., Kinukawa, N., Tsuneyoshi, M., Maehara, Y., Sugimachi, K. and Kuwano, M. (2015) Increased Expression of an ATP-Binding Cassette Superfamily Transporter, Multidrug Resistance Protein 2, in Human Colorectal Carcinomas. Clinical Cancer Research, 6, 2401-2407.
Yamasaki, M., Makino, T., Masuzawa, T., Kurokawa, Y., Miyata, H., Takiguchi, S., Nakajima, K., Fujiwara, Y., Matsuura, N., Mori, M., et al. (2011) Role of Multidrug Resistance Protein 2 (MRP2) in Chemoresistance and Clinical Outcome in Oesophageal Squamous Cell Carcinoma. British Journal of Cancer, 104, 707-713.
https://doi.org/10.1038/sj.bjc.6606071
Hirano, T., Kato, H., Maeda, M., Gong, Y., Shou, Y., Nakamura, M., Maeda, J., Yashima, K., Kato, Y., Akimoto, S., et al. (2005) Identification of Postoperative Adjuvant Chemotherapy Responders in Non-Small Cell Lung Cancer by Novel Biomarker. International Journal of Cancer, 117, 460-468.
https://doi.org/10.1002/ijc.21172
Kasahara, K., Fujiwara, Y., Nishio, K., Ohmori, T., Sugimoto, Y., Komiya, K., Matsuda, T. and Saijo, N. (1991) Metallothionein Content Correlates with the Sensitivity of Human Small Cell Lung Cancer Cell Lines to Cisplatin. Cancer Research, 51, 3237-3242.
Dasari, S. and Tchounwou, P.B. (2014) Cisplatin in Cancer Therapy: Molecular Mechanisms of Action. European Journal of Pharmacology, 740, 364-378.
https://doi.org/10.1016/j.ejphar.2014.07.025
Deloia, J.A., Bhagwat, N.R., Darcy, K.M., Strange, M., Tian, C., Nuttall, K., Krivak, T.C. and Niedernhofer, L.J. (2012) Comparison of ERCC1/XPF Genetic Variation, mRNA and Protein Levels in Women with Advanced Stage Ovarian Cancer Treated with Intraperitoneal Platinum. Gynecologic Oncology, 126, 448-454.
https://doi.org/10.1016/j.ygyno.2012.05.006
Li, Z., Qing, Y., Guan, W., Li, M., Peng, Y., Zhang, S., Xiong, Y. and Wang, D. (2014) Predictive Value of APE1, BRCA1, ERCC1 and TUBB3 Expression in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) Receiving First-Line Platinum-Paclitaxel Chemotherapy. Cancer Chemotherapy and Pharmacology, 74, 777-786. https://doi.org/10.1007/s00280-014-2562-1
Villalobos, M., Czapiewski, P., Reinmuth, N., Fischer, J.R., Andreas, S., Kortsik, C., Serke, M., Wolf, M., Neuser, P., Reuss, A., et al. (2018) ERCC1 Assessment in Upfront Treatment with and without Cisplatin-Based Chemotherapy in Stage IIIB/IV Non-Squamous Non-Small Cell Lung Cancer. Medical Oncology, 35, Article No. 106. https://doi.org/10.1007/s12032-018-1169-5
Zhang, Z., Jiang, C. and Hu, L. (2014) Low Expression of Excision Repair Cross-Complementation Group-1 Protein Predicts Better Outcome in Patients with Locally Advanced Nasopharyngeal Cancer Treated with Concurrent Chemoradiotherapy. Tumori Journal, 100, 328-332.
Ryu, H., Song, I.C., Choi, Y.S., Yun, H.J., Jo, D.Y., Kim, J.M., Ko, Y.B. and Lee, H.J. (2017) ERCC1 Expression Status Predicts the Response and Survival of Patients with Metastatic or Recurrent Cervical Cancer Treated via Platinum-Based Chemotherapy. Medicine, 96, e9402. https://doi.org/10.1097/MD.0000000000009402
Ma, X., Huang, J., Du, W., Zhuo, H., Zhang, J., Shi, C. and Liu, L. (2015) ERCC1 Plays an Important Role in Predicting Survival Outcomes and Treatment Response for Patients with HNSCC: A Meta-Analysis. Oral Oncology, 51, 483-492.
https://doi.org/10.1016/j.oraloncology.2015.02.094
Arts, H.J., Hollema, H., Lemstra, W., Willemse, P.H., De Vries, E.G., Kampinga, H.H. and Van der Zee, A.G. (1999) Heatshock-Protein-27 (hsp27) Expression in Ovarian Carcinoma: Relation in Response to Chemotherapy and Prognosis. International Journal of Cancer, 84, 234-238.
https://doi.org/10.1002/(SICI)1097-0215(19990621)84:3%3C234::AID-IJC6%3E3.0.CO;2-9
Liu, J.R., Opipari, A.W., Tan, L., Jiang, Y., Zhang, Y., Tang, H. and Nunez, G. (2002) Dysfunctional Apoptosome Activation in Ovarian Cancer: Implications for Chemoresistance. Cancer Research, 62, 924-931.
Vargas-Roig, L.M., Gago, F.E., Tello, O., Aznar, J.C. and Ciocca, D.R. (1998) Heat Shock Protein Expression and Drug Resistance in Breast Cancer Patients Treated with Induction Chemotherapy. International Journal of Cancer, 79, 468-475.
https://doi.org/10.1002/(SICI)1097-0215(19981023)79:5%3C468::AID-IJC4%3E3.0.CO;2-Z
Belfi, C.A., Chatterjee, S., Gosky, D.M., Berger, S.J. and Berger, N.A. (1999) Increased Sensitivity of Human Colon Cancer Cells to DNA Cross-Linking Agents after GRP78 Up-Regulation. Biochemical and Biophysical Research Communications, 257, 361-368. https://doi.org/10.1006/bbrc.1999.0472
Huang, T.G., Ip, S.M., Yeung, W.S. and Ngan, H.Y. (2000) Changes in p21WAF1, pRb, Mdm-2, Bax and Bcl-2 Expression in Cervical Cancer Cell Lines Transfected with a p53 Expressing Adenovirus. European Journal of Cancer, 36, 249-256.
https://doi.org/10.1016/S0959-8049(99)00247-6
Brozovic, A., Simaga, S. and Osmak, M. (2000) Induction of Heat Shock Protein 70 in Drug-Resistant Cells by Anticancer Drugs and Hyperthermia. Neoplasma, 48, 99-103.
Skvortsov, S., Dudas, J., Eichberger, P., Witsch-Baumgartner, M., Loeffler-Ragg, J., Pritz, C., Schartinger, V.H., Maier, H., Hall, J., Debbage, P., Riechelmann, H., Lukas, P. and Skvortsova, I. (2014) Rac1 as a Potential Therapeutic Target for Chemo-Radioresistant Head and Neck Squamous Cell Carcinomas (HNSCC). British Journal of Cancer, 110, 2677-2687. https://doi.org/10.1038/bjc.2014.221
Shen, D.W., Liang, X.J., Gawinowicz, M.A. and Gottesman, M.M. (2004) Identification of Cytoskeletal [14C] Carboplatin-Binding Proteins Reveals Reduced Expression and Disorganization of Actin and Filamin in Cisplatin-Resistant Cell Lines. Molecular Pharmacology, 66, 789-793. https://doi.org/10.1124/mol.66.4.789
Kurayoshi, M., Yamamoto, H., Izumi, S. and Kikuchi, A. (2007) Post-Translational Palmitoylation and Glycosylation of Wnt5a Are Necessary for Its Signaling. Biochemical Journal, 15, 515-523. https://doi.org/10.1042/BJ20061476
Hanaki, H., Yamamoto, H., Sakane, H., Matsumoto, S., Ohda, H., Sato, A. and Kikuchi, A. (2012) An Anti-Wnt5a Antibody Suppresses Metastasis of Gastric Cancer Cells in Vivo by Inhibiting Receptor-Mediated Endocytosis. Molecular Cancer Therapeutics, 11, 298-307. https://doi.org/10.1158/1535-7163.MCT-11-0682
Finne, J. and Mäkelä, P.H. (1985) Cleavage of the Polysialosyl Units of Brain Glycoproteins by a Bacteriophage Endosialidase. Involvement of a Long Oligosaccharide Segment in Molecular Interactions of Polysialic Acid. Journal of Biological Chemistry, 260, 1265-1270. https://doi.org/10.1016/S0021-9258(20)71238-X
Michon, F., Brisson, J.R. and Jennings, H.J. (1987) Conformational Differences between Linear Alpha (2-8)-Linked Homosialooligosaccharides and the Epitope of the Group B Meningococcal Polysaccharide. Biochemistry, 26, 8399-8405.
https://doi.org/10.1021/bi00399a055
Kabat, E.A., Liao, J., Osserman, E.F., Gamian, A., Michon, F. and Jennings, H.J. (1988) The Epitope Associated with the Binding of the Capsular Polysaccharide of the Group B. meningococcus and of Escherichia coli K1 to a Human Monoclonal Macroglobulin, IgMNOV. Journal of Experimental Medicine, 168, 699-711.
https://doi.org/10.1084/jem.168.2.699
Muller, D., Stoppini, L., Wang, C. and Kiss, J.Z. (1994) A Role for Polysialylated Neural Cell Adhesion Molecule in Lesion-Induced Sprouting in Hippocampal Organotypic Cultures. Neuroscience, 61, 441-445.
https://doi.org/10.1016/0306-4522(94)90424-3
Moloney, D.J. and Haltiwanger, R.S. (1999) The O-Linked Fucose Glycosylation Pathway: Identification and Characterization of a Uridine Diphosphoglucose: Fucose-1,3-glucosyltransferase Activity from Chinese Hamster Ovary Cells. Glycobiology, 9, 679-687. https://doi.org/10.1093/glycob/9.7.679
