厚朴酚誘導三陰性乳癌細胞凋亡並抑制上皮間質轉化

Magnolol Induces Apoptosis and Inhibits Epithelial-Mesenchymal Transition in Triple Negative Breast Cancer Cells

10.30185/SCMJ.202408_23(2).0002

朱世盟(Shih-Meng Chu)；王孝宇(Hsiao-Yu Wang)；蘇莉婷(Li-Ting Su)；潘以如(Yi-Ju Pan)

三陰性乳癌 ； 厚朴酚 ； 細胞凋亡 ； 上皮間質轉化 ； TNBC ； magnolol ； apoptosis ； EMT

秀傳醫學雜誌

23卷2期（2024 / 08 / 01）

156 - 164

繁體中文;英文

在三陰性乳癌（triple negative breast cancer, TNBC）中，上皮間質轉化（epithelial-mesenchymal transition, EMT）過程導致增加侵襲能力和對化學治療的抗藥性。厚朴酚（magnolol）是一種在植用物厚朴中發現的生物活性化合物，已報導可以減緩結腸癌細胞的EMT。然而，厚朴酚是否抑制TNBC細胞的EMT仍不清楚。因此，本研究的主要目的是驗證厚朴酚對TNBC細胞的EMT的影響。將TNBC MDA-MB-231和4T1細胞用不同濃度的厚朴酚處理48小時。使用流式細胞儀和西方墨點評估厚朴酚對細胞週期分佈和EMT相關蛋白的影響。結果顯示，厚朴酚明顯誘導TNBC細胞凋亡，降低N-cadherin、zinc finger E-box binding homeobox 1（ZEB1）、ZEB2、Snail、Slug和Twist的蛋白水平，同時增加E-cadherin的表現。從Kaplan-Meier plotter（KM plot）獲得的信息顯示，Snail水平較低的TNBC患者比Snail水平較高的患者有更有利的預後。誘導細胞凋亡和減少EMT相關蛋白可能參與厚朴酚介導的抗TNBC效應。

In triple-negative breast cancer (TNBC), the process of epithelial to mesenchymal transition (EMT) contributes to increased invasion ability and resistance to chemotherapy. Magnolol, a bioactive compound found in the medicinal plant Magnolia officinalis, has been reported to attenuate EMT of colon cancer cells. However, it is unclear whether magnolol inhibits EMT of TNBC cells. Therefore, the main goal of the present study was to verify the effect of magnolol on EMT in TNBC cells. Both TNBC MDA-MB-231 and 4T1 cells were treated with different concentrations of magnolol for 48 h. Effects of magnolol on cell cycle distribution and EMT-related proteins were evaluated by using flow cytometry and Western blotting assay. The results showed that magnolol significantly induced apoptosis and reduced protein levels of N-cadherin, zinc finger E-box binding homeobox 1 (ZEB1), ZEB2, Snail, Slug, and Twist, while increasing expression of E-cadherin. Information obtained from the Kaplan-Meier plotter (KM plot) indicated that TNBC patients with low levels of Snail had a more favorable prognosis compared to those with high levels. The anti-TNBC effects of magnolol may be attributed to the induction of apoptosis and the reduction of EMT-related proteins.

1. Liao PA, Chu PY, Tan ZL, Hsu FT, Lee YC, Wu HJ. STAT3 inactivation and induction of apoptosis associate with fluoxetine-inhibited epithelialmesenchymal transition and growth of triplenegative breast cancer. In Vivo. Anticancer Res. 2022;42:3807-14.
   連結：
2. Yin L, Duan JJ, Bian XW, Yu SC. Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res. 2020;22:61.
   連結：
3. Kaszak I, Witkowska-Piłaszewicz O, Niewiadomska Z, Dworecka-Kaszak B, Ngosa Toka F, Jurka P. Role of cadherins in Cancer-A Review. Int J Mol Sci. 2020; 21:7624.
   連結：
4. Göppel J, Möckelmann N, Münscher A, Sauter G, Schumacher U. Expression of epithelial-mesenchymal transition regulating transcription factors in head and neck squamous cell carcinomas. Anticancer Res. 2017;37:5435-40.
   連結：
5. Grasset EM, Dunworth M, Sharma G, Loth M, Tandurella J, Cimino-Mathews A, et al. Triple- negative breast cancer metastasis involves complex epithelial-mesenchymal transition dynamics and requires vimentin. Sci Transl Med. 2022;14: eabn7571.
   連結：
6. Zeng D, Liang YK, Xiao YS, Wei XL, Lin HY, Wu Y, et al. Inhibition of notch1 reverses EMT and chemoresistance to cisplatin via direct downregulation of MCAM in triple-negative breast cancer cells. Int J Cancer. 2020;147:490-504.
   連結：
7. Hashemi M, Arani HZ, Orouei S, Fallah S, Ghorbani A, Khaledabadi M, et al. EMT mechanism in breast cancer metastasis and drug resistance: Revisiting molecular interactions and biological functions. Biomed Pharmacother. 2022;155: 113774.
   連結：
8. Wang Y, Li JW, Qin YN, Sun CP, Chen JJ, Ruan YY, et al. Clinical observation on the effect of Chinese medicine-“TCM formula” intervention on recurrence and metastasis of triple negative breast cancer. Complement Ther Med. 2020;52: 102456.
   連結：
9. Zhao W, Liu J, Li Y, Chen Z, Qi D, Zhang Z. Immune effect of active components of traditional Chinese Medicine on triple-negative breast cancer. Front Pharmacol. 2021;12:731741.
   連結：
10. Niu L, Hou Y, Jiang M, Bai G. The rich pharmacological activities of Magnolia officinalis and secondary effects based on significant intestinal contributions. J Ethnopharmacol. 2021;281: 114524.
    連結：
11. Ranaware AM, Banik K, Deshpande V, Padmavathi G, Roy NK, Sethi G, et al. Magnolol: a neolignan from the magnolia family for the prevention and treatment of vancer. Int J Mol Sci. 2018;19:2362.
    連結：
12. Chei S, Oh HJ, Song JH, Seo YJ, Lee K, Lee BY. Magnolol suppresses TGF-β-induced epithelialto- mesenchymal transition in Human colorectal cancer cells. Front Oncol. 2019;9:752.
    連結：
13. Liu Y, Cao W, Zhang B, Liu YQ, Wang ZY, Wu YP, et al. The natural compound magnolol inhibits invasion and exhibits potential in human breast cancer therapy. Sci Rep. 2013;3: 3098.
    連結：
14. Lin CH, Lin KH, Ku HJ, Lee KC, Lin SS, Hsu FT. Amentoflavone induces caspase-dependent/- independent apoptosis and dysregulates cyclindependent kinase-mediated cell cycle in colorectal cancer in vitro and in vivo. Environ Toxicol. 2023. doi: 10.1002/tox.23749
    連結：
15. Nagy Á, Munkácsy G, Győrffy B. Pancancer survival analysis of cancer hallmark genes. Sci Rep. 2021;11:6047.
    連結：
16. Ősz Á, Lánczky A, Győrffy B. Survival analysis in breast cancer using proteomic data from four independent datasets. Sci Rep. 2021;11:16787.
    連結：
17. Plesca D, Mazumder S, Almasan A. DNA damage response and apoptosis. Methods Enzymol. 2008; 446:107-22.
    連結：
18. Su Z, Yang Z, Xu Y, Chen Y, Yu Q. Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol Cancer. 2015;14:48.
    連結：
19. Pfeffer CM, Singh ATK. Apoptosis: A Target for Anticancer Therapy. Int J Mol Sci. 2018;19:448.
    連結：
20. Mrozik KM, Blaschuk OW, Cheong CM, Zannettino ACW, Vandyke K. N-cadherin in cancer metastasis, its emerging role in haematological malignancies and potential as a therapeutic target in cancer. BMC Cancer. 2018;18:939.
    連結：
21. Gött H, Nagl J, Hagedorn F, Thomas S, Schwarm FP, Uhl E, et al. ZEB1 induces N-cadherin expression in human glioblastoma and may alter patient survival. Mol Clin Oncol. 2022;17:123.
    連結：
22. Wu K, Zeng J, Zhou J, Fan J, Chen Y, Wang Z, et al. Slug contributes to cadherin switch and malignant progression in muscle-invasive bladder cancer development. Urol Oncol. 2013;31:1751- 60.
    連結：
23. Liu SS, Qi J, Teng ZD, Tian FT, Lv XX, Li K, et al. Resistomycin attenuates triple-negative breast cancer progression by inhibiting E3 ligase Pellino-1 and inducing SNAIL/SLUG degradation. Signal Transduct Target Ther. 2020;5(1):133.
    連結：
24. Rhodes LV, Tate CR, Segar HC, Burks HE, Phamduy TB, Hoang V, et al. Suppression of triple-negative breast cancer metastasis by pan-DAC inhibitor panobinostat via inhibition of ZEB family of EMT master regulators. Breast Cancer Res Treat. 2014;145:593-604.
    連結：
25. Ferrari-Amorotti G, Chiodoni C, Shen F, Cattelani S, Soliera AR, Manzotti G, et al. Suppression of invasion and metastasis of triple-negative breast cancer lines by pharmacological or genetic inhibition of slug activity. Neoplasia. 2014;16:1047-58.
    連結：
26. Hsu LC, Kuo CY, Hsu FT, Chang HF, Ou JJ. Hyperforin suppresses oncogenic kinases and induces apoptosis in colorectal cancer cells. In Vivo. 2023;37:182-9.
27. Zhou Y, Bi Y, Yang C, Yang J, Jiang Y, Meng F, et al. Magnolol induces apoptosis in MCF-7 human breast cancer cells through G2/M phase arrest and caspase-independent pathway. Pharmazie. 2013;68:755-62.