Rekombinant klotho proteininin insan kolorektal kanser hücreleri üzerindeki apoptotik etkilerinin değerlendirilmesi
Abstract
Kolorektal kanser dünyada en sık görülen gastrointestinal kanser türüdür. Klotho, bedende fosfat ve kalsiyum homeostazının düzenlenmesinde önemli rol oynayan, hormon görevi de gören yaşlanma karşıtı glikozile edilmiş transmembran bir proteindir. Klotho sadece bir "yaşlanma baskılayıcı" olarak işlev görmez, aynı zamanda hücrenin hayatta kalmasını ve çoğalmasını da düzenler ve kanser metastazında rol oynayan potansiyel bir tümör baskılayıcı olarak görev yapar. Bu durum, kanser ve yaşlanmanın benzer moleküler özellikleri paylaştığı düşünüldüğünde, şaşırtıcı değildir. Akciğer, karaciğer, meme, pankreas, tiroid, over, böbrek ve kolon kanseri de dahil çeşitli kanserlerin patogenezinde, klotho proteinini eksprese eden gende, mutasyonlar tespit edilmiştir. Bu çalışmada hücre proliferasyonunda, tümör migrasyon ve invazyonunda önemli bir rol üstlenen rekombinant klotho (r-klotho) proteininin, apoptoza dirençli insan kolorektal kanser hücrelerine (Caco-2) farklı konsantrasyon (0,075µg/mL, 0,15µg/mL, 0,3µg/mL, 0,6µg/mL ve 0,9µg/mL) ve saatlerde (24 ve 48 saat) ekzojen olarak kültür besiyerine eklenerek uygulanmasının sağlıklı kolon (CCD 841 CoN) ve kanser hücreleri üzerindeki olası sitotoksik ve apoptotik etkilerini araştırmak amaçlandı. Bu amaç doğrultusunda ilk olarak kolorektal kanser hücrelerinin r-klotho ile muamelesi gerçekleştirildi. R-klothonun kanser ve sağlıklı hücreler üzerindeki in vitro canlılığa etkileri 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolium bromid (MTT) ve aktif kaspaz-3/7’nin flow sitometri analizleri ile değerlendirildi. Bulgularımız r-klothonun insan kolorektal kanser hücrelerinde hücre proliferasyonunu baskılamak ve hücre apoptozunu indüklemek yoluyla bir tümör baskılayıcı olarak çalıştığını ortaya koymuştur. Sonuç olarak klotho proteini, kolorektal kanser için terapötik girişimlerde yeni stratejilerin geliştirilebilmesi için, potansiyel antitümör bir ajan olarak kullanılabilir.
Supporting Institution
Eskişehir Osmangazi Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi
Project Number
202046043
References
- Zhang, X., Shi, H., Tang, H., Fang, Z., Wang, J., & Cui, S. (2015). miR-218 inhibits the invasion and migration of colon cancer cells by targeting the PI3K/Akt/mTOR signaling pathway. International journal of molecular medicine, 35(5), 1301-1308.
- Siegel, R. L., Miller, K. D., & Jemal, A. (2016). Cancer statistics, 2016. CA: a cancer journal for clinicians, 66(1), 7-30.
- Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., ... & Nabeshima, Y. I. (1997). Mutation of the mouse klotho gene leads to a syndrome resembling ageing. nature, 390(6655), 45-51.
- Kuro-o, M. (2018). Molecular mechanisms underlying accelerated aging by defects in the FGF23-klotho system. International journal of nephrology, 2018.
- Matsumura, Y., Aizawa, H., Shiraki-Iida, T., Nagai, R., Kuro-o, M., & Nabeshima, Y. I. (1998). Identification of the humanklothogene and its two transcripts encoding membrane and secretedklothoprotein. Biochemical and biophysical research communications, 242(3), 626-630.
- Yamamoto, M., Clark, J. D., Pastor, J. V., Gurnani, P., Nandi, A., Kurosu, H., ... & Kuro-o, M. (2005). Regulation of Oxidative Stress by the Anti-aging Hormone Klotho*♦. Journal of Biological Chemistry, 280(45), 38029-38034.
- Kuro-o, M. (2008). Klotho as a regulator of oxidative stress and senescence.
- Klotho, K. O. M. (2010). Pflugers archives. European Journal of Physiology, 459, 333-343.
- Urakawa, I., Yamazaki, Y., Shimada, T., Iijima, K., Hasegawa, H., Okawa, K., ... & Yamashita, T. (2006). Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature, 444(7120), 770-774.
- Abramovitz, L., Rubinek, T., Ligumsky, H., Bose, S., Barshack, I., Avivi, C., ... & Wolf, I. (2011). KL1 internal repeat mediates klotho tumor suppressor activities and inhibits bFGF and IGF-I signaling in pancreatic cancer. Clinical Cancer Research, 17(13), 4254-4266.
- Jiang, B., Gu, Y., & Chen, Y. (2014). Identification of novel predictive markers for the prognosis of pancreatic ductal adenocarcinoma. Cancer Investigation, 32(6), 218-225.
- Chen, C. D., Li, H., Liang, J., Hixson, K., Zeldich, E., & Abraham, C. R. (2015). The anti-aging and tumor suppressor protein Klotho enhances differentiation of a human oligodendrocytic hybrid cell line. Journal of Molecular Neuroscience, 55(1), 76-90.
- Camilli, T. C., Xu, M., O’Connell, M. P., Chien, B., Frank, B. P., Subaran, S., ... & Weeraratna, A. T. (2011). Loss of Klotho during melanoma progression leads to increased filamin cleavage, increased Wnt5A expression, and enhanced melanoma cell motility. Pigment cell & melanoma research, 24(1), 175-186.
- Wang, Y., Chen, L., Huang, G., He, D., He, J., Xu, W., ... & Wu, J. (2013). Klotho sensitizes human lung cancer cell line to cisplatin via PI3k/Akt pathway. PloS one, 8(2), e57391.
- Ibi, T., Usuda, J., Inoue, T., Sato, A., & Takegahara, K. (2017). Klotho expression is correlated to molecules associated with epithelial mesenchymal transition in lung squamous cell carcinoma. Oncology letters, 14(5), 5526-5532.
- Dai, X., Zhang, J., Arfuso, F., Chinnathambi, A., Zayed, M. E., Alharbi, S. A., ... & Sethi, G. (2015). Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy. Experimental Biology and Medicine, 240(6), 760-773.
- Lee, J., Jeong, D. J., Kim, J., Lee, S., Park, J. H., Chang, B., ... & Lee, M. S. (2010). The anti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma. Molecular cancer, 9(1), 1-10.
- Wolf, I., Levanon-Cohen, S., Bose, S., Ligumsky, H., Sredni, B., Kanety, H., ... & Rubinek, T. (2008). Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene, 27(56), 7094-7105.
- Rubinek, T., Shulman, M., Israeli, S., Bose, S., Avraham, A., Zundelevich, A., ... & Wolf, I. (2012). Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Breast cancer research and treatment, 133(2), 649-657.
- Shu, G., Xie, B., Ren, F., Liu, D. C., Zhou, J., Li, Q., ... & Zhou, J. (2013). Restoration of klotho expression induces apoptosis and autophagy in hepatocellular carcinoma cells. Cellular oncology, 36(2), 121-129.
- Xie, B., Zhou, J., Yuan, L., Ren, F., Liu, D. C., Li, Q., & Shu, G. (2013). Epigenetic silencing of Klotho expression correlates with poor prognosis of human hepatocellular carcinoma. Human pathology, 44(5), 795-801.
- Lojkin, I., Rubinek, T., Orsulic, S., Schwarzmann, O., Karlan, B. Y., Bose, S., & Wolf, I. (2015). Reduced expression and growth inhibitory activity of the aging suppressor klotho in epithelial ovarian cancer. Cancer letters, 362(2), 149-157.
- Turan, K., & Ata, P. (2011). Effects of intra-and extracellular factors on anti-aging klotho gene expression.
- Zhu, Y., Xu, L., Zhang, J., Xu, W., Liu, Y., Yin, H., ... & Lin, Z. (2013). K lotho suppresses tumor progression via inhibiting PI 3 K/A kt/GSK 3β/Snail signaling in renal cell carcinoma. Cancer science, 104(6), 663-671.
- Pan, J., Zhong, J., Gan, L. H., Chen, S. J., Jin, H. C., Wang, X., & Wang, L. J. (2011). Klotho, an anti-senescence related gene, is frequently inactivated through promoter hypermethylation in colorectal cancer. Tumor Biology, 32(4), 729-735.
- Xie, B., Chen, J., Liu, B., & Zhan, J. (2013). Klotho acts as a tumor suppressor in cancers. Pathology & Oncology Research, 19(4), 611-617.
- Zhou, X., Fang, X., Jiang, Y., Geng, L., Li, X., Li, Y., ... & Wang, X. (2017). Klotho, an anti-aging gene, acts as a tumor suppressor and inhibitor of IGF-1R signaling in diffuse large B cell lymphoma. Journal of hematology & oncology, 10(1), 1-11.
- Tang, X., Wang, Y., Fan, Z., Ji, G., Wang, M., Lin, J., ... & Meltzer, S. J. (2016). Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma. Laboratory investigation, 96(2), 197-205.
- Li, X. X., Huang, L. Y., Peng, J. J., Liang, L., Shi, D. B., Zheng, H. T., & Cai, S. J. (2014). Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway. International journal of oncology, 45(2), 611-618.
- Chen, B., Wang, X., Zhao, W., & Wu, J. (2010). Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549. Journal of Experimental & Clinical Cancer Research, 29(1), 1-7.
- Doi, S., Zou, Y., Togao, O., Pastor, J. V., John, G. B., Wang, L., ... & Kuro-o, M. (2011). Klotho inhibits transforming growth factor-β1 (TGF-β1) signaling and suppresses renal fibrosis and cancer metastasis in mice. Journal of Biological Chemistry, 286(10), 8655-8665.
- Sun, H., Gao, Y., Lu, K., Zhao, G., Li, X., Li, Z., & Chang, H. (2015). Overexpression of Klotho suppresses liver cancer progression and induces cell apoptosis by negatively regulating wnt/β-catenin signaling pathway. World journal of surgical oncology, 13(1), 1-8.
- Soyocak, A., & Koc, G. (2020). Effect of black grape extract on MMP-9 gene expression in breast cancer cells. Biological Diversity and Conservation, 13, 194-199.
Abstract
Colorectal cancer is the most common type of gastrointestinal cancer in the world. Klotho is an anti-aging glycosylated transmembrane protein that plays an important role in regulating phosphate and calcium homeostasis in the body and acts as a hormone. Klotho not only functions as a "suppressor of aging", but also regulates cell survival and proliferation and acts as a potential tumor suppressor that plays a role in cancer metastasis. Mutations in the gene expressing the klotho protein have been identified in the pathogenesis of various cancers, including lung, liver, breast, pancreatic, thyroid, ovarian, kidney, and colon cancer. In this study, recombinant klotho (r-klotho) protein, which plays an important role in cell proliferation, tumor migration and invasion, was detected in apoptosis-resistant human colorectal cancer cells (Caco-2) with different concentrations (0.075µg/mL, 0.15µg/mL, 0.3µg/mL, 0.6µg/mL, and 0.9µg/mL) and hours (24 and 48 hours). It was aimed to investigate the possible cytotoxic and apoptotic effects on the healthy colon (CCD 841 CoN) and cancer cells of exogenous application by adding to the culture medium. For this purpose, in the present study, for the first time, colorectal cancer cells were treated with r-klotho. The in vitro viability effects of r-klotho on cancer and healthy cells were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry analyses of active caspase-3/7. Our findings revealed that r-klotho works as a tumor suppressor by suppressing cell proliferation and inducing cell apoptosis in human colorectal cancer cells. Consequently, klotho protein can be used as a potential antitumor agent for the development of new strategies in therapeutic interventions for colorectal cancer.
Project Number
202046043
References
- Zhang, X., Shi, H., Tang, H., Fang, Z., Wang, J., & Cui, S. (2015). miR-218 inhibits the invasion and migration of colon cancer cells by targeting the PI3K/Akt/mTOR signaling pathway. International journal of molecular medicine, 35(5), 1301-1308.
- Siegel, R. L., Miller, K. D., & Jemal, A. (2016). Cancer statistics, 2016. CA: a cancer journal for clinicians, 66(1), 7-30.
- Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., ... & Nabeshima, Y. I. (1997). Mutation of the mouse klotho gene leads to a syndrome resembling ageing. nature, 390(6655), 45-51.
- Kuro-o, M. (2018). Molecular mechanisms underlying accelerated aging by defects in the FGF23-klotho system. International journal of nephrology, 2018.
- Matsumura, Y., Aizawa, H., Shiraki-Iida, T., Nagai, R., Kuro-o, M., & Nabeshima, Y. I. (1998). Identification of the humanklothogene and its two transcripts encoding membrane and secretedklothoprotein. Biochemical and biophysical research communications, 242(3), 626-630.
- Yamamoto, M., Clark, J. D., Pastor, J. V., Gurnani, P., Nandi, A., Kurosu, H., ... & Kuro-o, M. (2005). Regulation of Oxidative Stress by the Anti-aging Hormone Klotho*♦. Journal of Biological Chemistry, 280(45), 38029-38034.
- Kuro-o, M. (2008). Klotho as a regulator of oxidative stress and senescence.
- Klotho, K. O. M. (2010). Pflugers archives. European Journal of Physiology, 459, 333-343.
- Urakawa, I., Yamazaki, Y., Shimada, T., Iijima, K., Hasegawa, H., Okawa, K., ... & Yamashita, T. (2006). Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature, 444(7120), 770-774.
- Abramovitz, L., Rubinek, T., Ligumsky, H., Bose, S., Barshack, I., Avivi, C., ... & Wolf, I. (2011). KL1 internal repeat mediates klotho tumor suppressor activities and inhibits bFGF and IGF-I signaling in pancreatic cancer. Clinical Cancer Research, 17(13), 4254-4266.
- Jiang, B., Gu, Y., & Chen, Y. (2014). Identification of novel predictive markers for the prognosis of pancreatic ductal adenocarcinoma. Cancer Investigation, 32(6), 218-225.
- Chen, C. D., Li, H., Liang, J., Hixson, K., Zeldich, E., & Abraham, C. R. (2015). The anti-aging and tumor suppressor protein Klotho enhances differentiation of a human oligodendrocytic hybrid cell line. Journal of Molecular Neuroscience, 55(1), 76-90.
- Camilli, T. C., Xu, M., O’Connell, M. P., Chien, B., Frank, B. P., Subaran, S., ... & Weeraratna, A. T. (2011). Loss of Klotho during melanoma progression leads to increased filamin cleavage, increased Wnt5A expression, and enhanced melanoma cell motility. Pigment cell & melanoma research, 24(1), 175-186.
- Wang, Y., Chen, L., Huang, G., He, D., He, J., Xu, W., ... & Wu, J. (2013). Klotho sensitizes human lung cancer cell line to cisplatin via PI3k/Akt pathway. PloS one, 8(2), e57391.
- Ibi, T., Usuda, J., Inoue, T., Sato, A., & Takegahara, K. (2017). Klotho expression is correlated to molecules associated with epithelial mesenchymal transition in lung squamous cell carcinoma. Oncology letters, 14(5), 5526-5532.
- Dai, X., Zhang, J., Arfuso, F., Chinnathambi, A., Zayed, M. E., Alharbi, S. A., ... & Sethi, G. (2015). Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy. Experimental Biology and Medicine, 240(6), 760-773.
- Lee, J., Jeong, D. J., Kim, J., Lee, S., Park, J. H., Chang, B., ... & Lee, M. S. (2010). The anti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma. Molecular cancer, 9(1), 1-10.
- Wolf, I., Levanon-Cohen, S., Bose, S., Ligumsky, H., Sredni, B., Kanety, H., ... & Rubinek, T. (2008). Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene, 27(56), 7094-7105.
- Rubinek, T., Shulman, M., Israeli, S., Bose, S., Avraham, A., Zundelevich, A., ... & Wolf, I. (2012). Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Breast cancer research and treatment, 133(2), 649-657.
- Shu, G., Xie, B., Ren, F., Liu, D. C., Zhou, J., Li, Q., ... & Zhou, J. (2013). Restoration of klotho expression induces apoptosis and autophagy in hepatocellular carcinoma cells. Cellular oncology, 36(2), 121-129.
- Xie, B., Zhou, J., Yuan, L., Ren, F., Liu, D. C., Li, Q., & Shu, G. (2013). Epigenetic silencing of Klotho expression correlates with poor prognosis of human hepatocellular carcinoma. Human pathology, 44(5), 795-801.
- Lojkin, I., Rubinek, T., Orsulic, S., Schwarzmann, O., Karlan, B. Y., Bose, S., & Wolf, I. (2015). Reduced expression and growth inhibitory activity of the aging suppressor klotho in epithelial ovarian cancer. Cancer letters, 362(2), 149-157.
- Turan, K., & Ata, P. (2011). Effects of intra-and extracellular factors on anti-aging klotho gene expression.
- Zhu, Y., Xu, L., Zhang, J., Xu, W., Liu, Y., Yin, H., ... & Lin, Z. (2013). K lotho suppresses tumor progression via inhibiting PI 3 K/A kt/GSK 3β/Snail signaling in renal cell carcinoma. Cancer science, 104(6), 663-671.
- Pan, J., Zhong, J., Gan, L. H., Chen, S. J., Jin, H. C., Wang, X., & Wang, L. J. (2011). Klotho, an anti-senescence related gene, is frequently inactivated through promoter hypermethylation in colorectal cancer. Tumor Biology, 32(4), 729-735.
- Xie, B., Chen, J., Liu, B., & Zhan, J. (2013). Klotho acts as a tumor suppressor in cancers. Pathology & Oncology Research, 19(4), 611-617.
- Zhou, X., Fang, X., Jiang, Y., Geng, L., Li, X., Li, Y., ... & Wang, X. (2017). Klotho, an anti-aging gene, acts as a tumor suppressor and inhibitor of IGF-1R signaling in diffuse large B cell lymphoma. Journal of hematology & oncology, 10(1), 1-11.
- Tang, X., Wang, Y., Fan, Z., Ji, G., Wang, M., Lin, J., ... & Meltzer, S. J. (2016). Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma. Laboratory investigation, 96(2), 197-205.
- Li, X. X., Huang, L. Y., Peng, J. J., Liang, L., Shi, D. B., Zheng, H. T., & Cai, S. J. (2014). Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway. International journal of oncology, 45(2), 611-618.
- Chen, B., Wang, X., Zhao, W., & Wu, J. (2010). Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549. Journal of Experimental & Clinical Cancer Research, 29(1), 1-7.
- Doi, S., Zou, Y., Togao, O., Pastor, J. V., John, G. B., Wang, L., ... & Kuro-o, M. (2011). Klotho inhibits transforming growth factor-β1 (TGF-β1) signaling and suppresses renal fibrosis and cancer metastasis in mice. Journal of Biological Chemistry, 286(10), 8655-8665.
- Sun, H., Gao, Y., Lu, K., Zhao, G., Li, X., Li, Z., & Chang, H. (2015). Overexpression of Klotho suppresses liver cancer progression and induces cell apoptosis by negatively regulating wnt/β-catenin signaling pathway. World journal of surgical oncology, 13(1), 1-8.
- Soyocak, A., & Koc, G. (2020). Effect of black grape extract on MMP-9 gene expression in breast cancer cells. Biological Diversity and Conservation, 13, 194-199.
Details
| Primary Language | Turkish |
|---|---|
| Subjects | Biochemistry and Cell Biology (Other) |
| Journal Section | Research Articles |
| Authors | |
| Project Number | 202046043 |
| Early Pub Date | August 3, 2022 |
| Publication Date | August 15, 2022 |
| Submission Date | April 19, 2022 |
| Acceptance Date | May 17, 2022 |
| Published in Issue | Year 2022 Volume: 15 Issue: 2 |
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