Investigation of Apoptotic Effect of Klotho Protein on Human Colorectal Cancer Cells via TRAIL Death Receptors
Year 2022,
, 324 - 337, 30.12.2022
Sibel Gunes
Onur Uysal
Merve Nur Soykan
Ayla Eker Sarıboyacı
Abstract
Klotho is a transmembrane protein which is deficiency has pleiotropic effects in a number of aging-related disease processes and various cancers. In some recent studies about klotho protein disorders, it has been shown to klotho is effective in various cancers including lung, liver, breast, kidney, and colon. TNF-related apoptosis-inducing ligand (TRAIL), a TNF family molecule, is a cytokine that stimulates apoptosis through death receptors in many cancer types and therefore attracts attention for tumor therapies in various preclinical models. Interaction with TRAIL death receptors create an apoptotic effect in cancer treatments by reducing the proliferation of cancer cells. In this study, it was aimed to investigate the effects of exogen klotho administration on cell viability and apoptosis on TRAIL death receptors (TRAIL1 and TRAILR2) in human healthy colon cells (CCD 841 CoN) and TRAIL-resistant human colorectal cancer cells (caco2). For this purpose, cells were treated with different concentrations of klotho for 24 and 48 hours. To determine the cell viability, proliferation, and death receptors effects of klotho protein on cancer and healthy cells evaluations with WST-8 and Real-Time qRT-PCR analysis were performed. Our results showed that the increase in klotho protein concentration did not have a significant effect on cell viability in healthy colon cells, whereas it decreased cell viability and proliferation in apoptosis-resistant human colorectal cancer cells. Relative gene expression of TRAIL1 and TRAILR2 death receptors increased with klotho applied to the apoptosis-resistant colorectal cancer cell line caco-2. Therefore, targeting the ligand-receptors that induce TNF-related apoptosis with the klotho protein can be considered as a potential therapeutic approach for cancer therapy.
Supporting Institution
Eskişehir Osmangazi Üniversitesi
Project Number
ESOGU-BAP, Kod: 202046A113
Thanks
This study was supported by grants Eskisehir Osmangazi University, Scientific Research Projects (ESOGU-BAP, Code: 202046A113).
References
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Klotho proteinin insan kolorektal kanser hücreleri üzerindeki apoptotik etkisinin TRAIL ölüm reseptörleri üzerinden incelenmesi
Year 2022,
, 324 - 337, 30.12.2022
Sibel Gunes
Onur Uysal
Merve Nur Soykan
Ayla Eker Sarıboyacı
Abstract
Klotho, eksikliği bir dizi yaşlanma ile ilişkili hastalık sürecinde ve çeşitli kanserlerde pleiotropik etkilere sahip olan bir transmembran proteindir. Klotho protein bozuklukları ile ilgili son zamanlarda yapılan bazı araştırmalarda klothonun akciğer, karaciğer, meme, böbrek ve kolon dahil çeşitli kanserlerde etkili olduğu gösterilmiştir. Tümör nekroz faktör ilişkili apoptoz indükleyici ligand (TRAIL), birçok kanser türünde ölüm reseptörleri aracılığıyla apoptozu uyaran bir sitokindir ve bu nedenle çeşitli preklinik modellerde tümör terapileri için dikkat çekmektedir. TRAIL ölüm reseptörleri ile etkileşim, kanser hücrelerinin çoğalmasını azaltarak kanser tedavilerinde apoptotik bir etki yaratır. Bu çalışmada, eksojen klotho uygulamasının insan sağlıklı kolon (CCD 841 CoN) ve TRAIL dirençli insan kolorektal kanser hücreleri (Caco-2) üzerindeki hücre canlılığı ve apoptoz üzerine etkilerinin TRAIL ölüm reseptörleri (TRAIL1 ve TRAILR2) aracılığı ile araştırılması amaçlanmıştır. Bu amaçla hücreler, 24 ve 48 saat boyunca farklı konsantrasyonlarda klotho ile muamele edildi. Klotho proteinin kanser ve sağlıklı hücreler üzerindeki hücre canlılığı, proliferasyonu ve ölüm reseptörlerinin etkilerini belirlemek için WST-8 ve real-time qRT-PCR analizi ile değerlendirmeler yapıldı. Sonuçlarımız, klotho protein konsantrasyonundaki artışın sağlıklı kolon hücrelerinde hücre canlılığı üzerinde önemli bir etkiye sahip olmadığını, apoptoza dirençli insan kolorektal kanser hücrelerinde ise hücre canlılığını ve proliferasyonunu azalttığını gösterdi. Apoptoza dirençli kolorektal kanser hücre dizisi Caco-2'ye uygulanan klotho ile TRAIL1 ve TRAILR2 ölüm reseptörlerinin göreceli gen ekspresyonu arttı. Sonuç olarak, TRAIL ölüm reseptörlerinin klotho proteini ile hedeflenmesi kolorektal kanser tedavisi için potansiyel bir terapötik yaklaşım olarak kabul edilebilir.
Project Number
ESOGU-BAP, Kod: 202046A113
References
- Zhou, X., Wang X., Klotho: a novel biomarker for cancer. J Cancer Res Clin Oncol. 2015;141(6):961-9. doi: 10.1007/s00432-014-1788-y.
- Tang, X., Wang, Y., Fan, Z., Ji, G., Wang, M., Lin, J., Huang, S., Meltzer, SJ., Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma. Lab Invest. 2016;96(2):197-205. doi: 10.1038/labinvest.2015.86.
- Shu, G., Xie, B., Ren, F., Liu, DC., Zhou, J., Li, Q., Chen, J., Yuan, L., Zhou, J., Restoration of klotho expression induces apoptosis and autophagy in hepatocellular carcinoma cells. Cell Oncol (Dordr). 2013;36(2):121-9. doi: 10.1007/s13402-012-0118-0.
- Chen, B., Wang, X., Zhao, W., Wu, J., Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549. J Exp Clin Cancer Res. 2010;29(1):99. doi: 10.1186/1756-9966-29-99.
- Li, XX., Huang, LY., Peng, JJ., Liang, L., Shi, DB., Zheng, HT., Cai, SJ., Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway. Int J Oncol. 2014;45(2):611-8. doi: 10.3892/ijo.2014.2430.
- Hu, MC., Shi, M., Zhang, J., Quiñones, H., Griffith, C., Kuro-o, M., Moe, OW., Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2011;22(1):124-36. doi: 10.1681/ASN.2009121311.
- Gunes, S., Soykan, MN., Sariboyaci, AE., Uysal, O., Sevimli, TS., Enhancement of Apo2L/TRAIL signaling pathway receptors by the activation of Klotho gene with CRISPR/Cas9 in Caco-2 colon cancer cells. Med Oncol. 2021;38(12):146. doi: 10.1007/s12032-021-01595-7.
- Zhou, X., Chen, K., Lei, H., Sun, Z., Klotho gene deficiency causes salt-sensitive hypertension via monocyte chemotactic protein-1/CC chemokine receptor 2-mediated inflammation. J Am Soc Nephrol. 2015;26(1):121-32. doi: 10.1681/ASN.2013101033.
- Matsumura, Y., Aizawa, H., Shiraki-Iida, T., Nagai, R., Kuro-o, M., Nabeshima, Y., Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun. 1998;242(3):626-30. doi: 10.1006/bbrc.1997.8019.
- Shiraki-Iida, T., Aizawa, H., Matsumura, Y., Sekine, S., Iida, A., Anazawa, H., Nagai, R., Kuro-o, M., Nabeshima, Y., Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett. 1998;424(1-2):6-10. doi: 10.1016/s0014-5793(98)00127-6.
- Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., Iwasaki, H., Iida, A., Shiraki-Iida, T., Nishikawa, S., Nagai, R., Nabeshima, YI., Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;6;390(6655):45-51. doi: 10.1038/36285.
- Imura, A., Tsuji, Y., Murata, M., Maeda, R., Kubota, K., Iwano, A., Obuse, C., Togashi, K., Tominaga, M., Kita, N., Tomiyama, K., Iijima, J., Nabeshima, Y., Fujioka, M., Asato, R., Tanaka, S., Kojima, K., Ito, J., Nozaki, K., Hashimoto., N, Ito., T, Nishio., T, Uchiyama., T, Fujimori., T, Nabeshima., Y., alpha-Klotho as a regulator of calcium homeostasis. Science. 2007; 316(5831):1615-8. doi: 10.1126/science.1135901.
- Hu, MC., Shi, M., Zhang, J., Pastor, J., Nakatani, T., Lanske, B., Razzaque, MS., Rosenblatt, KP., Baum, MG., Kuro-o, M., Moe, OW., Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J. 2010;24(9):3438-50. doi: 10.1096/fj.10-154765.
- Urakawa, I, Yamazaki, Y, Shimada, T, Iijima, K, Hasegawa, H, Okawa, K, Fujita, T, Fukumoto, S, Yamashita, T., Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444(7120):770-4. doi: 10.1038/nature05315.
- Ben-Dov, IZ., Galitzer, H., Lavi-Moshayoff, V., Goetz, R., Kuro-o, M., Mohammadi, M., Sirkis, R., Naveh-Many, T., Silver J., The parathyroid is a target organ for FGF23 in rats. J Clin Invest. 2007;117(12):4003-8. doi: 10.1172/JCI32409.
- Ritter, CS., Zhang, S., Delmez, J., Finch, JL., Slatopolsky, E., Differential expression and regulation of Klotho by paricalcitol in the kidney, parathyroid, and aorta of uremic rats. Kidney Int. 2015;87(6):1141-52. doi: 10.1038/ki.2015.22.
- Pan, J., Zhong, J., Gan, LH., Chen, SJ., Jin, HC., Wang, X., Wang, LJ., Klotho, an anti-senescence related gene, is frequently inactivated through promoter hypermethylation in colorectal cancer. Tumour Biol. 2011;32(4):729-35. doi: 10.1007/s13277-011-0174-5.
- Ligumsky, H., Rubinek, T., Merenbakh-Lamin, K., Yeheskel, A., Sertchook, R., Shahmoon, S., Aviel-Ronen, S., Wolf I., Tumor Suppressor Activity of Klotho in Breast Cancer Is Revealed by Structure-Function Analysis. Mol Cancer Res. 2015;13(10):1398-407. doi: 10.1158/1541-7786.MCR-15-0141.
- Refaat, A., Abd-Rabou, A., Reda, A., TRAIL combinations: The new 'trail' for cancer therapy (Review). Oncol Lett. 2014;7(5):1327-1332. doi: 10.3892/ol.2014.1922.
- Corazza, N., Kassahn, D., Jakob, S., Badmann, A., Brunner, T., TRAIL-induced apoptosis: between tumor therapy and immunopathology. Ann N Y Acad Sci. 2009;1171:50-8. doi: 10.1111/j.1749-6632.2009.04905.x.
- Ma, L., Wei, HL., Wang, KJ., Meng, XY., Ni, SQ., Zhou, C., Li, Y., Yu, R., Ma, Q., Rhein promotes TRAIL-induced apoptosis in bladder cancer cells by up-regulating DR5 expression. Aging (Albany NY). 2022;14(16):6642-6655. doi: 10.18632/aging.204236.
- R, Mishra DP., Trailing TRAIL Resistance: Novel Targets for TRAIL Sensitization in Cancer Cells. Front Oncol. 2015;5:69. doi: 10.3389/fonc.2015.00069.
- Yildiz, Y., Yaylim-Eraltan, I., Arikan, S., Ergen, H.A., Küçücük, S., Isbir, T., Is there any correlation between TNF-related apoptosis-inducing ligand (TRAIL) genetic variants and breast cancer? Arch Med Sci. 2010;6(6):932-6. doi: 10.5114/aoms.2010.19304.
- van Geelen, CM., Pennarun, B., Le, PT., de Vries, EG., de Jong, S., Modulation of TRAIL resistance in colon carcinoma cells: different contributions of DR4 and DR5. BMC Cancer. 2011;11:39. doi: 10.1186/1471-2407-11-39.
- Li, X.B., Deng, Y.G., Hu, J.P., Wang, Z., Xie, R.Z., Luo, H., Hu, X.Y., Resveratrol overcomes TRAIL resistance in human colon cancer cells. Bangladesh Journal of Pharmacology, 2015;10(3), 568-576. doi: 10.3329/bjp.v10i3.21208.
- Stoddart, MJ., WST-8 analysis of cell viability during osteogenesis of human mesenchymal stem cells. Methods Mol Biol. 2011;740:21-5. doi: 10.1007/978-1-61779-108-6_4.
- Sun, H., Gao, Y., Lu, K., Zhao, G., Li, X., Li, Z., Chang, H., Overexpression of Klotho suppresses liver cancer progression and induces cell apoptosis by negatively regulating wnt/β-catenin signaling pathway. World J Surg Oncol. 2015 Oct 24;13:307. doi: 10.1186/s12957-015-0717-0. PMID: 26499380; PMCID: PMC4619481.
- Chen, C.D., Li, H., Liang, J., Hixson, K., Zeldich, E., Abraham, C.R., The anti-aging and tumor suppressor protein Klotho enhances differentiation of a human oligodendrocytic hybrid cell line. J Mol Neurosci. 2015 Jan;55(1):76-90. doi: 10.1007/s12031-014-0336-1. Epub 2014 Jun 8. PMID: 24907942; PMCID: PMC5154549.
- Sariboyaci, A.E, Uysal, O., Soykan, M.N., Gunes, S. ,The potential therapeutic effect of klotho on cell viability in human colorectal adenocarcinoma HT-29 cells. Med Oncol. 2022 Sep 7;39(12):191. doi: 10.1007/s12032-022-01793-x. PMID: 36071274.
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