Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Licochalcone D Inhibits Skin Epidermal Cells Transformation through the Regulation of AKT Signaling Pathways

  • Sun-Young Hwang (College of Korean Medicine, Dongshin University) ;
  • Kwanhwan Wi (College of Korean Medicine, Dongshin University) ;
  • Goo Yoon (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Cheol-Jung Lee (Research Center for Materials Analysis, Korea Basic Science Institute) ;
  • Soong-In Lee (College of Korean Medicine, Dongshin University) ;
  • Jong-gil Jung (College of Korean Medicine, Dongshin University) ;
  • Hyun-Woo Jeong (College of Korean Medicine, Dongshin University) ;
  • Jeong-Sang Kim (College of Korean Medicine, Dongshin University) ;
  • Chan-Heon Choi (College of Korean Medicine, Dongshin University) ;
  • Chang-Su Na (College of Korean Medicine, Dongshin University) ;
  • Jung-Hyun Shim (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Mee-Hyun Lee (College of Korean Medicine, Dongshin University)
  • Received : 2023.09.12
  • Accepted : 2023.10.10
  • Published : 2023.11.01
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Abstract

Cell transformation induced by epidermal growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetate (TPA) is a critical event in cancer initiation and progression, and understanding the underlying mechanisms is essential for the development of new therapeutic strategies. Licorice extract contains various bioactive compounds, which have been reported to have anticancer and anti-inflammatory effects. This study investigated the cancer preventive efficacy of licochalcone D (LicoD), a chalcone derivative in licorice extract, in EGF and TPA-induced transformed skin keratinocyte cells. LicoD effectively suppressed EGF-induced cell proliferation and anchorage-independent colony growth. EGF and TPA promoted the S phase of cell cycle, while LicoD treatment caused G1 phase arrest and down-regulated cyclin D1 and up-regulated p21 expression associated with the G1 phase. LicoD also induced apoptosis and increased apoptosis-related proteins such as cleaved-caspase-3, cleaved-caspase-7, and Bax (Bcl2-associated X protein). We further investigated the effect of LicoD on the AKT signaling pathway involved in various cellular processes and found decreased p-AKT, p-GSK3β, and p-NFκB expression. Treatment with MK-2206, an AKT pharmacological inhibitor, suppressed EGF-induced cell proliferation and transformed colony growth. In conclusion, this study demonstrated the potential of LicoD as a preventive agent for skin carcinogenesis.

Keywords

Acknowledgement

This work was supported by a Korea Innovation Foundation (INNIPOLIS) grant funded by the Korean government (Ministry of Science and ICT) through a science and technology project that opens the future of the region, grant number: 2021-DD-UP-0380, the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (No. 2022R1A5A2029546) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2020R1I1A3070556). This research was supported by the Dongshin University research grants.

References

  1. Aggarwal, V., Tuli, H. S., Tania, M., Srivastava, S., Ritzer, E. E., Pandey, A., Aggarwal, D., Barwal, T. S., Jain, A., Kaur, G., Sak, K., Varol, M. and Bishayee, A. (2022) Molecular mechanisms of action of epigallocatechin gallate in cancer: recent trends and advancement. Semin. Cancer Biol. 80, 256-275. https://doi.org/10.1016/j.semcancer.2020.05.011
  2. Chatterjee, N. and Alfaro-Moreno, E. (2023) In vitro cell transformation assays: a valuable approach for carcinogenic potentiality assessment of nanomaterials. Int. J. Mol. Sci. 24, 8219.
  3. Deng, N., Qiao, M., Li, Y., Liang, F., Li, J. and Liu, Y. (2023) Anticancer effects of licochalcones: a review of the mechanisms. Front. Pharmacol. 14, 1074506.
  4. Dias, M. C., Pinto, D. and Silva, A. M. S. (2021) Plant flavonoids: chemical characteristics and biological activity. Molecules 26, 5377.
  5. Fu, X., Zhao, R., Yoon, G., Shim, J. H., Choi, B. Y., Yin, F., Xu, B., Laster, K. V., Liu, K., Dong, Z. and Lee, M. H. (2021) 3-Deoxysappanchalcone inhibits skin cancer proliferation by regulating T-lymphokine-activated killer cell-originated protein kinase in vitro and in vivo. Front. Cell Dev. Biol. 9, 638174.
  6. Fu, Y., Chen, J., Li, Y. J., Zheng, Y. F. and Li, P. (2013) Antioxidant and anti-inflammatory activities of six flavonoids separated from licorice. Food Chem. 141, 1063-1071. https://doi.org/10.1016/j.foodchem.2013.03.089
  7. Gao, F., Li, M., Yu, X., Liu, W., Zhou, L. and Li, W. (2021) Licochalcone A inhibits EGFR signalling and translationally suppresses survivin expression in human cancer cells. J. Cell. Mol. Med. 25, 813-826. https://doi.org/10.1111/jcmm.16135
  8. Gartel, A. L. and Tyner, A. L. (2002) The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol. Cancer Ther. 1, 639-649.
  9. Giordano, A. and Tommonaro, G. (2019) Curcumin and cancer. Nutrients 11, 2376.
  10. Hwang, S. Y., Chae, J. I., Kwak, A. W., Lee, M. H. and Shim, J. H. (2020) Alternative options for skin cancer therapy via regulation of AKT and related signaling pathways. Int. J. Mol. Sci. 21, 6869.
  11. Islam, M. R., Akash, S., Rahman, M. M., Nowrin, F. T., Akter, T., Shohag, S., Rauf, A., Aljohani, A. S. M. and Simal-Gandara, J. (2022) Colon cancer and colorectal cancer: prevention and treatment by potential natural products. Chem. Biol. Interact. 368, 110170.
  12. Karimian, A., Ahmadi, Y. and Yousefi, B. (2016) Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair. (Amst.) 42, 63-71. https://doi.org/10.1016/j.dnarep.2016.04.008
  13. Kimura, I., Kagawa, S., Tsuneki, H., Tanaka, K. and Nagashima, F. (2022) Multitasking bamboo leaf-derived compounds in prevention of infectious, inflammatory, atherosclerotic, metabolic, and neuropsychiatric diseases. Pharmacol. Ther. 235, 108159.
  14. Kwak, A. W., Kim, W. K., Lee, S. O., Yoon, G., Cho, S. S., Kim, K. T., Lee, M. H., Choi, Y. H., Lee, J. Y., Park, J. W. and Shim, J. H. (2023) Licochalcone B induces ROS-dependent apoptosis in oxaliplatin-resistant colorectal cancer cells via p38/JNK MAPK signaling. Antioxidants (Basel) 12, 656.
  15. Liskova, A., Samec, M., Koklesova, L., Brockmueller, A., Zhai, K., Abdellatif, B., Siddiqui, M., Biringer, K., Kudela, E., Pec, M., Gadanec, L. K., Sudomova, M., Hassan, S. T. S., Zulli, A., Shakibaei, M., Giordano, F. A., Busselberg, D., Golubnitschaja, O. and Kubatka, P. (2021) Flavonoids as an effective sensitizer for anti-cancer therapy: insights into multi-faceted mechanisms and applicability towards individualized patient profiles. EPMA J. 12, 155-176. https://doi.org/10.1007/s13167-021-00242-5
  16. Maria Pia, G. D., Sara, F., Mario, F. and Lorenza, S. (2019) Biological effects of licochalcones. Mini Rev. Med. Chem. 19, 647-656. https://doi.org/10.2174/1389557518666180601095420
  17. Montalto, F. I. and De Amicis, F. (2020) Cyclin D1 in cancer: a molecular connection for cell cycle control, adhesion and invasion in tumor and stroma. Cells 9, 2648.
  18. Mori, S., Chang, J. T., Andrechek, E. R., Matsumura, N., Baba, T., Yao, G., Kim, J. W., Gatza, M., Murphy, S. and Nevins, J. R. (2009) Anchorage-independent cell growth signature identifies tumors with metastatic potential. Oncogene 28, 2796-2805. https://doi.org/10.1038/onc.2009.139
  19. Nomura, M., Ichimatsu, D., Moritani, S., Koyama, I., Dong, Z., Yokogawa, K. and Miyamoto, K. (2005) Inhibition of epidermal growth factor-induced cell transformation and Akt activation by caffeine. Mol. Carcinog. 44, 67-76. https://doi.org/10.1002/mc.20120
  20. Oh, H. N., Lee, M. H., Kim, E., Kwak, A. W., Yoon, G., Cho, S. S., Liu, K., Chae, J. I. and Shim, J. H. (2020) Licochalcone D induces ROS-dependent apoptosis in gefitinib-sensitive or resistant lung cancer cells by targeting EGFR and MET. Biomolecules 10, 297.
  21. Park, K. H., Joo, S. H., Seo, J. H., Kim, J., Yoon, G., Jeon, Y. J., Lee, M. H., Chae, J. I., Kim, W. K. and Shim, J. H. (2022) Licochalcone H induces cell cycle arrest and apoptosis in human skin cancer cells by modulating JAK2/STAT3 signaling. Biomol. Ther. (Seoul) 30, 72-79. https://doi.org/10.4062/biomolther.2021.149
  22. Park, M. R., Kim, S. G., Cho, I. A., Oh, D., Kang, K. R., Lee, S. Y., Moon, S. M., Cho, S. S., Yoon, G., Kim, C. S., Oh, J. S., You, J. S., Kim, D. K., Seo, Y. S., Im, H. J. and Kim, J. S. (2015) Licochalcone-A induces intrinsic and extrinsic apoptosis via ERK1/2 and p38 phosphorylation-mediated TRAIL expression in head and neck squamous carcinoma FaDu cells. Food Chem. Toxicol. 77, 34-43. https://doi.org/10.1016/j.fct.2014.12.013
  23. Pathak, K., Pathak, M. P., Saikia, R., Gogoi, U., Sahariah, J. J., Zothantluanga, J. H., Samanta, A. and Das, A. (2022) Cancer chemotherapy via natural bioactive compounds. Curr Drug Discov. Technol. 19, e310322202888.
  24. Prabhu, D. S., Selvam, A. P. and Rajeswari, V. D. (2018) Effective anti-cancer property of Pouteria sapota leaf on breast cancer cell lines. Biochem. Biophys. Rep. 15, 39-44.
  25. Ren, B., Kwah, M. X., Liu, C., Ma, Z., Shanmugam, M. K., Ding, L., Xiang, X., Ho, P. C., Wang, L., Ong, P. S. and Goh, B. C. (2021) Resveratrol for cancer therapy: challenges and future perspectives. Cancer Lett. 515, 63-72. https://doi.org/10.1016/j.canlet.2021.05.001
  26. Scaria, B., Sood, S., Raad, C., Khanafer, J., Jayachandiran, R., Pupulin, A., Grewal, S., Okoko, M., Arora, M., Miles, L. and Pandey, S. (2020) Natural health products (NHP's) and natural compounds as therapeutic agents for the treatment of cancer; mechanisms of anti-cancer activity of natural compounds and overall trends. Int. J. Mol. Sci. 21, 8480.
  27. Schmitt, E., Steyaert, A., Cimoli, G. and Bertrand, R. (1998) Bax-alpha promotes apoptosis induced by cancer chemotherapy and accelerates the activation of caspase 3-like cysteine proteases in p53 double mutant B lymphoma Namalwa cells. Cell Death Differ. 5, 506-516. https://doi.org/10.1038/sj.cdd.4400376
  28. Seo, J. H., Choi, H. W., Oh, H. N., Lee, M. H., Kim, E., Yoon, G., Cho, S. S., Park, S. M., Cho, Y. S., Chae, J. I. and Shim, J. H. (2019) Licochalcone D directly targets JAK2 to induced apoptosis in human oral squamous cell carcinoma. J. Cell. Physiol. 234, 1780-1793. https://doi.org/10.1002/jcp.27050
  29. Shafabakhsh, R. and Asemi, Z. (2019) Quercetin: a natural compound for ovarian cancer treatment. J. Ovarian Res. 12, 55.
  30. Si, L., Yan, X., Hao, W., Ma, X., Ren, H., Ren, B., Li, D., Dong, Z. and Zheng, Q. (2018) Licochalcone D induces apoptosis and inhibits migration and invasion in human melanoma A375 cells. Oncol. Rep. 39, 2160-2170.
  31. Siddiqui, A. J., Jahan, S., Singh, R., Saxena, J., Ashraf, S. A., Khan, A., Choudhary, R. K., Balakrishnan, S., Badraoui, R., Bardakci, F. and Adnan, M. (2022) Plants in anticancer drug discovery: from molecular mechanism to chemoprevention. Biomed. Res. Int. 2022, 5425485.
  32. Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A. and Bray, F. (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209-249. https://doi.org/10.3322/caac.21660
  33. Tewari, D., Patni, P., Bishayee, A., Sah, A. N. and Bishayee, A. (2022) Natural products targeting the PI3K-Akt-mTOR signaling pathway in cancer: a novel therapeutic strategy. Semin. Cancer Biol. 80, 1-17. https://doi.org/10.1016/j.semcancer.2019.12.008
  34. Uzoigwe, J. and Sauter, E. R. (2012) Cancer prevention and treatment using combination therapy with plant- and animal-derived compounds. Expert Rev. Clin. Pharmacol. 5, 701-709. https://doi.org/10.1586/ecp.12.62
  35. Wang, Z., Liu, Z., Cao, Y., Paudel, S., Yoon, G. and Cheon, S. H. (2013) Short and efficient synthesis of licochalcone B and D through acid-mediated claisen-schmidt condensation. Bull. Korean Chem. Soc. 34, 3906-3908. https://doi.org/10.5012/bkcs.2013.34.12.3906
  36. Wu, M. H., Chiu, Y. F., Wu, W. J., Wu, P. L., Lin, C. Y., Lin, C. L., Hsieh, Y. H. and Liu, C. J. (2018) Synergistic antimetastatic effect of cotreatment with licochalcone A and sorafenib on human hepatocellular carcinoma cells through the inactivation of MKK4/JNK and uPA expression. Environ. Toxicol. 33, 1237-1244. https://doi.org/10.1002/tox.22630
  37. Xue, L., Zhang, W. J., Fan, Q. X. and Wang, L. X. (2018) Licochalcone A inhibits PI3K/Akt/mTOR signaling pathway activation and promotes autophagy in breast cancer cells. Oncol. Lett. 15, 1869-1873.