Silibinin induces oral cancer cell apoptosis and reactive oxygen species generation by activating the JNK/c-Jun pathway

Zhang, Haibo; Kim, Hyeonjin; Kim, Si-Yong; Hai, Huang; Kim, Eungyung; Ma, Lei; Kim, Dongwook; Kim, Chae Yeon; Park, Kanghyun; Park, Sijun; Ko, Jiwon; Kim, Eun-Kyong; Kim, Kirim; Ryoo, Zae Young; Yi, Junkoo; Kim, Myoung Ok

doi:10.7150/jca.84734

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International Journal of Biological Sciences

International Journal of Medical Sciences

Theranostics

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J Cancer 2023; 14(10):1875-1887. doi:10.7150/jca.84734 This issue Cite

Research Paper

Silibinin induces oral cancer cell apoptosis and reactive oxygen species generation by activating the JNK/c-Jun pathway

Haibo Zhang^1,2†, Hyeonjin Kim^1†, Si-Yong Kim^3†, Huang Hai¹, Eungyung Kim¹, Lei Ma¹, Dongwook Kim¹, Chae Yeon Kim¹, Kanghyun Park¹, Sijun Park³, Jiwon Ko³, Eun-Kyong Kim⁴, Kirim Kim⁴, Zae Young Ryoo³, Junkoo Yi^5,✉, Myoung Ok Kim^1,✉

1. Department of Animal Science and Biotechnology, Research Center for Horse industry, Kyungpook National University, Sangju-si, Republic of Korea.
2. College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
3. School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, Korea.
4. Department of Dental Hygiene, Kyungpook National University, Sangju, Republic of Korea.
5. School of Animal Life Convergence Science, Hankyong National University, Anseong, 17579, Republic of Korea.
^†These authors contributed equally to this study.

Citation:

Zhang H, Kim H, Kim SY, Hai H, Kim E, Ma L, Kim D, Kim CY, Park K, Park S, Ko J, Kim EK, Kim K, Ryoo ZY, Yi J, Kim MO. Silibinin induces oral cancer cell apoptosis and reactive oxygen species generation by activating the JNK/c-Jun pathway. J Cancer 2023; 14(10):1875-1887. doi:10.7150/jca.84734. https://www.jcancer.org/v14p1875.htm

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Abstract

Background: Oral cancer is one of the most prevalent malignant tumors worldwide. Silibinin has been reported to exert therapeutic effects in various cancer models. However, its mechanism of action in oral cancer remains unclear. We aimed to examine the molecular processes underlying the effects of silibinin in oral cancer in vitro and in vivo as well as its potential anticancer effects. Next, we investigated the molecular processes underlying both in vitro and in vivo outcomes of silibinin treatment on oral cancer.

Methods: To investigate the effects of silibinin on the growth of oral cancer cells, cell proliferation and anchorage-independent colony formation tests were conducted on YD10B and Ca9-22 oral cancer cells. The effects of silibinin on the migration and invasion of oral cancer cells were evaluated using transwell assays. Flow cytometry was used to examine apoptosis, cell cycle distribution, and accumulation of reactive oxygen species (ROS). The molecular mechanism underlying the anticancer effects of silibinin was explored using immunoblotting. The in vivo effects of silibinin were evaluated using a Ca9-22 xenograft mouse model.

Results: Silibinin effectively suppressed YD10B and Ca9-22 cell proliferation and colony formation in a dose-dependent manner. Moreover, it induced cell cycle arrest in the G0/G1 phase, apoptosis, and ROS generation in these cells. Furthermore, silibinin inhibited the migration and invasion abilities of YD10B and Ca9-22 cells by regulating the expression of proteins involved in the epithelial-mesenchymal transition. Western blotting revealed that silibinin downregulated SOD1 and SOD2 and triggered the JNK/c-Jun pathway in oral cancer cells. Silibinin significantly inhibited xenograft tumor growth in nude mice, with no obvious toxicity.

Conclusions: Silibinin considerably reduced the development of oral cancer cells by inducing apoptosis, G₀/G₁ arrest, ROS generation, and activation of the JNK/c-Jun pathway. Importantly, silibinin effectively suppressed xenograft tumor growth in nude mice. Our findings indicate that silibinin may be a promising option for the prevention or treatment of oral cancer.

Keywords: Silibinin, ROS, JNK, Oral cancer, Xenograft

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APA

Zhang, H., Kim, H., Kim, S.Y., Hai, H., Kim, E., Ma, L., Kim, D., Kim, C.Y., Park, K., Park, S., Ko, J., Kim, E.K., Kim, K., Ryoo, Z.Y., Yi, J., Kim, M.O. (2023). Silibinin induces oral cancer cell apoptosis and reactive oxygen species generation by activating the JNK/c-Jun pathway. Journal of Cancer, 14(10), 1875-1887. https://doi.org/10.7150/jca.84734.

ACS

Zhang, H.; Kim, H.; Kim, S.Y.; Hai, H.; Kim, E.; Ma, L.; Kim, D.; Kim, C.Y.; Park, K.; Park, S.; Ko, J.; Kim, E.K.; Kim, K.; Ryoo, Z.Y.; Yi, J.; Kim, M.O. Silibinin induces oral cancer cell apoptosis and reactive oxygen species generation by activating the JNK/c-Jun pathway. J. Cancer 2023, 14 (10), 1875-1887. DOI: 10.7150/jca.84734.

NLM

CSE

Zhang H, Kim H, Kim SY, Hai H, Kim E, Ma L, Kim D, Kim CY, Park K, Park S, Ko J, Kim EK, Kim K, Ryoo ZY, Yi J, Kim MO. 2023. Silibinin induces oral cancer cell apoptosis and reactive oxygen species generation by activating the JNK/c-Jun pathway. J Cancer. 14(10):1875-1887.

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