Caffeic acid hinders the proliferation and migration through inhibition of IL-6 mediated JAK-STAT-3 signaling axis in human prostate cancer
Abstract
Caffeic acid (CA) is considered a promising phytochemical that has inhibited numerous cancer cell proliferation. Therefore, it is gaining increasing attention due to its safe and pharmacological applications. In this study, we investigated the role of CA in inhibiting the Interleukin-6 (IL-6)/Janus kinase (JAK)/Signal transducer and activator of transcription-3 (STAT-3) mediated suppression of the proliferation signaling in human prostate cancer cells.
The role of CA in proliferation and colony formation abilities was studied using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay and colony formation assays. Tumour cell death and cell cycle arrest were identified using flow cytometry techniques. CA treatment-associated protein expression of mitogen-activated protein kinase (MAPK) families, IL-6/JAK/STAT-3, proliferation, and apoptosis protein expressions in PC-3 and LNCaP cell lines were measured using Western blot investigation.
We have obtained that treatment with CA inhibits prostate cancer cells (PC-3 and LNCaP) proliferation and induces reactive oxygen species (ROS), cell cycle arrest, and apoptosis cell death in a concentration-dependent manner. Moreover, CA treatment alleviates the expression phosphorylated form of MAPK families, i.e., extracellular signal-regulated kinase 1 (ERK1), c-Jun N-terminal kinase (JNK), and p38 in PC-3 cells. IL-6 mediated JAK/STAT3 expressions regulate the proliferation and antiapoptosis that leads to prostate cancer metastasis and migration. Therefore, to mitigate the expression of IL-6/JAK/STAT-3 is considered an important target for the treatment of prostate cancer. In this study, we have observed that CA inhibits the expression of IL-6, JAK1, and phosphorylated STAT-3 in both PC-3 and LNCaP cells. Due to the inhibitory effect of IL-6/JAK/STAT-3, it resulted in decreased expression of cyclin-D1, cyclin-D2, and CDK1 in both PC-3 cells. In addition, CA induces apoptosis by enhancing the expression of Bax and caspase-3; and decreased expression of Bcl-2 in prostate cancer cells.
Thus, CA might act as a therapeutical application against prostate cancer by targeting the IL-6/JAK/STAT3 signaling axis.
Keywords
References
Rawla, P. (2019). Epidemiology of prostate cancer. World Journal of Oncology, 10(2), 63–89. https://doi.org/10.14740/wjon1191
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A. et al. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394–424. https://doi.org/10.3322/caac.2149
Zhu, Y., Wang, H. K., Qu, Y. Y., Ye, D. W. (2015). Prostate cancer in East Asia: Evolving trend over the last decade. Asian Journal of Andrology, 17(1), 48–57. https://doi.org/10.4103/1008-682X.132780
Taitt, H. E. (2018). Global trends and prostate cancer: A review of incidence, detection, and mortality as influenced by race, ethnicity, and geographic location. American Journal of Men’s Health, 12(6), 1807–1823. https://doi.org/10.1177/1557988318798279
Sekhoacha, M., Riet, K., Motloung, P., Gumenku, L., Adegoke, A. et al. (2022). Prostate cancer review: Genetics, diagnosis, treatment options, and alternative approaches. Molecules, 27(17), 5730. https://doi.org/10.3390/molecules27175730
Xu, R., Hu, J. (2020). The role of JNK in prostate cancer progression and therapeutic strategies. Biomedecine & Pharmacotherapie, 121, 109679. https://doi.org/10.1016/j.biopha.2019.109679
Noguchi, H. (2019). Regulation of c-Jun NH2-terminal kinase for islet transplantation. Journal of Clinical Medicine, 8(11), 1763. https://doi.org/10.3390/jcm8111763
Jimenez-Vacas, J. M., Herrero-Aguayo, V., Gomez-Gomez, E., Leon-Gonzalez, A. J., Saez-Martinez, P. et al. (2019). Luque. Spliceospme component SF3B1 as novel prognostic biomarker and therapeutic target for prostate cancer. Translational Research, 212, 89–103. https://doi.org/10.1016/j.trsl.2019.07.00
Braicu, C., Buse, M., Busuioc, C., Drula, R., Gulei, D. et al. (2019). A comprehensive review on MAPK: A promising therapeutic target in cancer. Cancers, 11(10), 1618. https://doi.org/10.3390/cancers11101618
Gao, P., Niu, N., Wei, T., Tozawa, H., Chen, X. et al. (2017). The roles of signal transducer and activator of transcription factor 3 in tumor angiogenesis. Oncotarget, 8(40), 69139–69161. https://doi.org/10.18632/oncotarget.19932
Wang, H. Q., Man, Q. W., Huo, F. Y., Gao, X., Lin, H. et al. (2020). STAT3 pathway in cancers: Past, present, and future. Med Communications, 3(2), e124. https://doi.org/10.1002/mco2.124
Manore, S. G., Doheny, D. L., Wong, G. L., Lo, H. W. (2022). IL-6/JAK/STAT3 signaling in breast cancer metastasis: Biology and treatment. Frontiers in Oncology, 12, 866014. https://doi.org/10.3389/fonc.2022.866014
Culig, Z. (2014). Proinflammatory cytokine interleukin-6 in prostate carcinogenesis. American Journal of Clinical and Experimental Urology, 2(3), 231–238
Crozier, L., Foy, R., Mouery, B. L., Whitaker, R. H., Corno, A. et al. (2022). CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal. The EMBO Journal, 41(6), e108599. https://doi.org/10.15252/embj.2021108599
Panda, S. K., Ray, S., Nayak, S., Behera, S., Bhanja, S. et al. (2019). A review on cell cycle checkpoints in relation to cancer. The Journal of Medical Sciences, 5, 88–95. https://doi.org/10.5005/jp-journals-10045-0013
Bayat Mokhtari, R., Homayouni, T. S., Baluch, N., Morgatskaya, E., Kumar, S. et al. (2017). Combination therapy in combating cancer. Oncotarget, 8(23), 38022–38043. https://doi.org/10.18632/oncotarget.16723
Jain, A., Madu, C. O., Lu, Y. (2021). Phytochemicals in chemoprevention: A cost effective complementary approach. Journal of Cancer, 12(12), 3686–3700. https://doi.org/10.7150/jca.57776
Monteiro Espindola, K. M., Ferreira, R. G., Mosquera Narvaez, L. E., Rocha Silva Rosario, A. C., Machado da Silva, A. H. et al. (2019). Chemical and pharmacological aspects of caffeic acid and its activity in hepatocarcinoma. Frontiers in Oncology, 9, 541. https://doi.org/10.3389/fonc.2019.00541
Maity, S., Kinra, M., Nampoothiri, M., Arora, D., Pai, K. S. R. et al. (2022). Caffeic acid, a dietary polyphenol, as a promising candidate for combination therapy. Chemical Papers, 76, 1271–1283. https://doi.org/10.1007/s11696-021-01947-
Balupillai, A., Prasad, R. N., Ramasamy, K., Muthusamy, G., Shanmugham, M. et al. (2015). Caffeic acid inhibits UVB-induced inflammation and photocarcinogenesis through activation of peroxisome proliferator-activated receptor-γ in mouse skin. Photochemistry and Photobiology, 91(6), 1458–1468. https://doi.org/10.1111/php.12522
Tseng, J. C., Wang, B. J., Wang, Y. P., Kuo, Y. Y., Chen, J. K. et al. (2023). Caffeic acid phenethyl ester suppresses EGFR/FAK/Akt signaling, migration, and tumor growth of prostate cancer cells. Phytomedicine, 116, 154860. https://doi.org/10.1016/j.phymed.2023.154860
Agilan, B., Rajendra Prasad, N., Kanimozhi, G., Karthikeyan, R., Ganesan, M. et al. (2016). Caffeic acid inhibits chronic UVB-induced cellular proliferation through JAK-STAT3 signaling in mouse skin. Photochemistry and Photobiology, 92(3), 467–474. https://doi.org/10.1111/php.12588
Chuu, C. P., Lin, H. P., Ciaccio, M. F., Kokontis, J. M., HauseJr, R. J. et al. (2012). Caffeic acid phenethyl ester suppresses the proliferation of human prostate cancer cells through inhibition of p70S6K and Akt signaling networks. Cancer Prevention Research, 2012(5), 788–797. https://doi.org/10.1158/1940-6207.CAPR-12-0004-T
Lin, H. P., Lin, C. Y., Huo, C., Hsiao, P. H., Su, L. C. et al. (2015). Caffeic acid phenethyl ester induced cell cycle arrest and growth inhibition in androgen-independent prostate cancer cells via regulation of Skp2, p53, p21Cip1 and p27Kip1. Oncotarget, 6(9), 6684. https://doi.org/10.18632/oncotarget.3246
Natarajan, K., Singh, S., Burke, T. R., Grunberger, D., Aggarwal, B. B. (1996). Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-Kappa B. Proceedings of the National Academy of Sciences of the United States of America, 93(17), 9090–9095. https://doi.org/10.1073/pnas.93.17.9090
Yang, G., Fu, Y., Malakhova, M., Kurinov, I., Zhu, F. et al. (2014). Caffeic acid directly targets ERK1/2 to attenuate solar UV-induced skin carcinogenesis. Cancer Prevention Research, 7(10), 1056–1066. https://doi.org/10.1158/1940-6207.CAPR-14-0141
Whongsiri, P., Phoyen, S., Boonla, C. (2018). Oxidative stress in urothelial carcinogenesis: Measurement of protein carbonylation and intracellular production of reactive oxygen species. Urothelial Carcinoma, 1655, 109–117. https://doi.org/10.1007/978-1-4939-7234-0_9
Mahmood, T., Yang, P. C. (2012). Western blot: Technique, theory, and trouble shooting. American Journal of Medical Sciences, 4(9), 429–434. https://doi.org/10.4103/1947-2714.100998
Mattiuzzi, C., Lippi, G. (2019). Current cancer epidemiology. Journal of Epidemiology and Global Health, 9(4), 217–222. https://doi.org/10.2991/jegh.k.191008.001
Sadrkhanloo, M., Paskeh, M. D. A., Hashemi, M., Raesi, R., Motahhary, M. et al. (2023). STAT3 signaling in prostate cancer progression and therapy resistance: An oncogenic pathway with diverse functions. Biomedicine and Pharmacotherapy, 158, 114168. https://doi.org/10.1016/j.biopha.2022.114168
Serafim, T. L., Carvalho, F. S., Marques, M. P., Calheiros, R., Silva, T. et al. (2011). Lipophilic caffeic and ferulic acid derivatives presenting cytotoxicity against human breast cancer cells. Chemical Research in Toxicology, 24(5), 763–774. https://doi.org/10.1021/tx200126r
Balupillai, A., Nagarajan, R. P., Ramasamy, K., Govindasamy, K., Muthusamy, G. (2018). Caffeic acid prevents UVB radiation induced photocarcinogenesis through regulation of PTEN signaling in human dermal fibroblasts and mouse skin. Toxicology and Applied Pharmacology, 352, 87–96. https://doi.org/10.1016/j.taap.2018.05.030
Ranjan, A., Ramachandran, S., Gupta, N., Kaushik, I., Wright, S. et al. (2019). Role of phytochemicals in cancer prevention. International Journal of Molecular Sciences, 20(20), 4981. https://doi.org/10.3390/ijms20204981
Nita, M., Grzybowski, A. (2016). The role of the reactive oxygen species and oxidative stress in the pathomechanism of the age-related ocular diseases and other pathologies of anterior and posterior eye segments in adults. Oxidative Medicine and Cellular Longevity, 2016, 3164734. https://doi.org/10.1155/2016/3164734
Kuczler, M. D., Olseen, A. M., Pienta, K. J., Amend, S. R. (2021). ROS—induced cell cycle arrest as a mechanism of resistance in polyaneuploid cancer cells (PACCs). Progress in Biophysics and Molecular Biology, 165, 3–7. https://doi.org/10.1016/j.pbiomolbio.2021.05.002
Chang, W. C., Hsieh, C. H., Hsiao, M. W., Lin, W. C., Hung, Y. C. et al. (2010). Caffeic acid induces apoptosis in human cervical cancer cells through the mitochondrial pathway. Taiwanese Journal of Obstetrics & Gynecology, 49(4), 419–424. https://doi.org/10.1016/S1028-4559(10)60092-7
Kabała-Dzik, A., Rzepecka-Stojko, A., Kubina, R., Jastrzębska-Stojko, Ż., Stojko, R. et al. (2017). Comparison of two components of propolis: Caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) induce apoptosis and cell cycle arrest of breast cancer cells MDA-MB-231. Molecules, 22(9), 1554. https://doi.org/10.3390/molecules22091554
Sun, J., Nan, G. (2016). The mitogen activated protein kinase (MAPK) signaling pathway as a discovery target in stroke. Journal of Molecular Neuroscience, 59, 90–98. https://doi.org/10.1007/s12031-016-0717-8
Pessoa, J., Martins, M., Casimiro, S., Plasencia, C. P., Barmatz, V. S. (2022). Editorial: Altered expression of proteins in cancer: Function and potential therapeutic targets. Frontiers in oncology, 12, 949139. https://doi.org/10.3389/fonc.2022.949139
Rezaei, P. F., Fouladdel, S., Ghaffari, S. M., Amin, G., Azizi, E. (2012). Induction of G1 cell cycle arrest and cyclin D1 down regulation in response to pericarp extract of Baneh in human breast cancer T47D cells. DARU Journal of Pharmaceutical Sciences, 20(1), 101. https://doi.org/10.1186/2008-2231-20-101
Pfeffer, C. M., Singh, A. T. K. (2018). Apoptosis: A target for anticancer therapy. International Journal of Molecular Sciences, 19(2), 448. https://doi.org/10.3390/ijms19020448
Tosic, I., Frank, D. A. (2021). STAT3 as a mediator of oncogenic cellular metabolism: Pathogenic and therapeutic implications. Neoplasia, 23(12), 1167–1178. https://doi.org/10.1016/j.neo.2021.10.003
Park, K. W., Kundu, J., Chae, I. G., Kim, D. H., Yu, M. H. et al. (2014). Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells. International Journal of Oncology, 19(2), 1309–1315. https://doi.org/10.3892/ijo.2014.2281
Kim, D. H., Park, J. E., Chae, I. G., Park, G., Lee, S. et al. (2017). Isoliquiritigenin inhibits the proliferation of human renal carcinoma Caki cells through the ROS-mediated regulation of Jak2/STAT3 pathway. Oncology Reports, 38(1), 575–583. https://doi.org/10.3892/or.2017.5677
京公网安备11010802044758号