Abstract
Honokiol (HNK), an active compound isolated from traditional Chinese medicine Magnolia officinalis, has shown potent anticancer activities. In the present study, we investigated the effects of HNK on breast cancer metastasis in vitro and in vivo, as well as the underlying molecular mechanisms. We showed that HNK (10−70 μmol/L) dose-dependently inhibited the viability of human mammary epithelial tumor cell lines MCF7, MDA-MB-231, and mouse mammary tumor cell line 4T1. In the transwell and scratch migration assays, HNK (10, 20, 30 μmol/L) dose-dependently suppressed the invasion and migration of the breast cancer cells. We demonstrated that HNK (10−50 μmol/L) dose-dependently upregulated the epithelial marker E-cadherin and downregulated the mesenchymal markers such as Snail, Slug, and vimentin at the protein level in breast cancer cells. Using a puromycin incorporation assay, we showed that HNK decreased the Snail translation efficiency in the breast cancer cells. In a mouse model of tumor metastasis, administration of HNK (50 mg/kg every day, intraperitoneal (i.p.), 6 times per week for 30 days) significantly decreased the number of metastatic 4T1 cell-derived nodules and ameliorated the histological alterations in the lungs. In addition, HNK-treated mice showed decreased Snail expression and increased E-cadherin expression in metastatic nodules. In conclusion, HNK inhibits EMT in the breast cancer cells by downregulating Snail and Slug protein expression at the mRNA translation level. HNK has potential as an integrative medicine for combating breast cancer by targeting EMT.
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References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.
DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin. 2017;67:439–48.
Mahalingaiah PK, Ponnusamy L, Singh KP. Chronic oxidative stress leads to malignant transformation along with acquisition of stem cell characteristics, and epithelial to mesenchymal transition in human renal epithelial cells. J Cell Physiol. 2015;230:1916–28.
Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265–73.
Brabletz T, Kalluri R, Nieto MA, Weinberg RA. EMT in cancer. Nat Rev Cancer. 2018;18:128–34.
De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13:97–110.
Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138:645–59.
Davis FM, Stewart TA, Thompson EW, Monteith GR. Targeting EMT in cancer: opportunities for pharmacological intervention. Trends Pharmacol Sci. 2014;35:479–88.
Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol. 2017;14:611–29.
Zhang Y, Chen T, Yuan P, Tian R, Hu W, Tang Y, et al. Encapsulation of honokiol into self-assembled pectin nanoparticles for drug delivery to HepG2 cells. Carbohydr Polym. 2015;133:31–8.
Averett C, Bhardwaj A, Arora S, Srivastava SK, Khan MA, Ahmad A, et al. Honokiol suppresses pancreatic tumor growth, metastasis and desmoplasia by interfering with tumor-stromal cross-talk. Carcinogenesis. 2016;37:1052–61.
Zhang Q, Zhao W, Ye C, Zhuang J, Chang C, Li Y, et al. Honokiol inhibits bladder tumor growth by suppressing EZH2/miR-143 axis. Oncotarget. 2015;6:37335–48.
Zhang Y, Ren X, Shi M, Jiang Z, Wang H, Su Q, et al. Downregulation of STAT3 and activation of MAPK are involved in the induction of apoptosis by HNK in glioblastoma cell line U87. Oncol Rep. 2014;32:2038–46.
Avtanski DB, Nagalingam A, Kuppusamy P, Bonner MY, Arbiser JL, Saxena NK, et al. Honokiol abrogates leptin-induced tumor progression by inhibiting Wnt1-MTA1-beta-catenin signaling axis in a microRNA-34a dependent manner. Oncotarget. 2015;6:16396–410.
Liu SH, Lee WJ, Lai DW, Wu SM, Liu CY, Tien HR, et al. Honokiol confers immunogenicity by dictating calreticulin exposure, activating ER stress and inhibiting epithelial-to-mesenchymal transition. Mol Oncol. 2015;9:834–49.
Avtanski DB, Nagalingam A, Bonner MY, Arbiser JL, Saxena NK, Sharma D. Honokiol inhibits epithelial-mesenchymal transition in breast cancer cells by targeting signal transducer and activator of transcription 3/Zeb1/E-cadherin axis. Mol Oncol. 2014;8:565–80.
Bando T, Ishimaru Y, Kida T, Hamada Y, Matsuoka Y, Nakamura T, et al. Analysis of RNA-Seq data reveals involvement of JAK/STAT signalling during leg regeneration in the cricket Gryllus bimaculatus. Development. 2013;140:959–64.
Lv XQ, Qiao XR, Su L, Chen SZ. Honokiol inhibits EMT-mediated motility and migration of human non-small cell lung cancer cells in vitro by targeting c-FLIP. Acta Pharmacol Sin. 2016;37:1574–86.
Wang N, Wang Z, Nie S, Song L, He T, Yang S, et al. Biodegradable polymeric micelles coencapsulating paclitaxel and honokiol: a strategy for breast cancer therapy in vitro and in vivo. Int J Nanomed. 2017;12:1499–514.
Avtanski DB, Nagalingam A, Bonner MY, Arbiser JL, Saxena NK, Sharma D. Honokiol activates LKB1-miR-34a axis and antagonizes the oncogenic actions of leptin in breast cancer. Oncotarget. 2015;6:29947–62.
Wang H, Wang HS, Zhou BH, Li CL, Zhang F, Wang XF, et al. Epithelial-mesenchymal transition (EMT) induced by TNF-alpha requires AKT/GSK-3beta-mediated stabilization of snail in colorectal cancer. PLoS ONE. 2013;8:e56664.
Sun M, Guo X, Qian X, Wang H, Yang C, Brinkman KL, et al. Activation of the ATM-Snail pathway promotes breast cancer metastasis. J Mol Cell Biol. 2012;4:304–15.
Cicchini C, Amicone L, Alonzi T, Marchetti A, Mancone C, Tripodi M. Molecular mechanisms controlling the phenotype and the EMT/MET dynamics of hepatocyte. Liver Int. 2015;35:302–10.
Li X, Chen H, Liu Z, Ye Z, Gou S, Wang C. Overexpression of MIST1 reverses the epithelial-mesenchymal transition and reduces the tumorigenicity of pancreatic cancer cells via the Snail/E-cadherin pathway. Cancer Lett. 2018;431:96–104.
Hao L, Ha JR, Kuzel P, Garcia E, Persad S. Cadherin switch from E- to N-cadherin in melanoma progression is regulated by the PI3K/PTEN pathway through Twist and Snail. Br J Dermatol. 2012;166:1184–97.
Xu M, Li J, Wang X, Meng S, Shen J, Wang S, et al. MiR-22 suppresses epithelial-mesenchymal transition in bladder cancer by inhibiting Snail and MAPK1/Slug/vimentin feedback loop. Cell Death Dis. 2018;9:209.
Fried LE, Arbiser JL. Honokiol, a multifunctional antiangiogenic and antitumor agent. Antioxid Redox Signal. 2009;11:1139–48.
Arora S, Singh S, Piazza GA, Contreras CM, Panyam J, Singh AP. Honokiol: a novel natural agent for cancer prevention and therapy. Curr Mol Med. 2012;12:1244–52.
Banerjee P, Basu A, Arbiser JL, Pal S. The natural product honokiol inhibits calcineurin inhibitor-induced and Ras-mediated tumor promoting pathways. Cancer Lett. 2013;338:292–9.
Yao CJ, Lai GM, Yeh CT, Lai MT, Shih PH, Chao WJ, et al. Honokiol eliminates human oral cancer stem-like cells accompanied with suppression of Wnt/ beta-catenin signaling and apoptosis induction. Evid Based Complement Altern Med. 2013;2013:146136.
Kaufhold S, Bonavida B. Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention. J Exp Clin Cancer Res. 2014;33:62.
Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000;2:84–9.
Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2:76–83.
Pan HC, Lai DW, Lan KH, Shen CC, Wu SM, Chiu CS, et al. Honokiol thwarts gastric tumor growth and peritoneal dissemination by inhibiting Tpl2 in an orthotopic model. Carcinogenesis. 2013;34:2568–79.
Cai J, Guan H, Fang L, Yang Y, Zhu X, Yuan J, et al. MicroRNA-374a activates Wnt/beta-catenin signaling to promote breast cancer metastasis. J Clin Invest. 2013;123:566–79.
Chengye W, Yu T, Ping S, Deguang S, Keyun W, Yan W, et al. Metformin reverses bFGF-induced epithelial-mesenchymal transition in HCC cells. Oncotarget. 2017;8:104247–57.
Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, et al. A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;25:666–81.
Iwasaki K, Ninomiya R, Shin T, Nomura T, Kajiwara T, Hijiya N, et al. Chronic hypoxia-induced slug promotes invasive behavior of prostate cancer cells by activating expression of ephrin-B1. Cancer Sci. 2018;109:3159–70.
Nguyen LT, Song YW, Cho SK. Baicalein inhibits epithelial to mesenchymal transition via downregulation of Cyr61 and LOXL-2 in MDA-MB231 breast cancer cells. Mol Cells. 2016;39:909–14.
Song L, Guo J, Chang R, Peng X, Li J, Xu X, et al. LKB1 obliterates Snail stability and inhibits pancreatic cancer metastasis in response to metformin treatment. Cancer Sci. 2018;109:1382–92.
Lv C, Wu X, Wang X, Su J, Zeng H, Zhao J, et al. The gene expression profiles in response to 102 traditional Chinese medicine (TCM) components: a general template for research on TCMs. Sci Rep. 2017;7:352.
Clavarino G, Claudio N, Couderc T, Dalet A, Judith D, Camosseto V, et al. Induction of GADD34 is necessary for dsRNA-dependent interferon-beta production and participates in the control of Chikungunya virus infection. PLoS Pathog. 2012;8:e1002708.
Han K, Jaimovich A, Dey G, Ruggero D, Meyuhas O, Sonenberg N, et al. Parallel measurement of dynamic changes in translation rates in single cells. Nat Methods. 2014;11:86–93.
Acknowledgements
This research was supported by grants from the National Natural Science Foundation of China (81373437, 81702934, and 81621064), CAMS Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-02-002), and “Significant New Drug Development” Major Science and Technology Development Projects of China (No. 2018ZX09711001-007-002).
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SZC designed the study. WDW, YS and YL performed the animal and related studies. WDW conducted the other experiments and wrote the paper. SZC edited the paper. All the authors read and approved the final manuscript.
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Wang, Wd., Shang, Y., Li, Y. et al. Honokiol inhibits breast cancer cell metastasis by blocking EMT through modulation of Snail/Slug protein translation. Acta Pharmacol Sin 40, 1219–1227 (2019). https://doi.org/10.1038/s41401-019-0240-x
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DOI: https://doi.org/10.1038/s41401-019-0240-x
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