Exploration of targets and molecular mechanisms of cinnamaldehyde in overcoming fulvestrant-resistant breast cancer: a bioinformatics study

Hermawan A., Putri H., Utomo R.Y.

Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, 55281, Indonesia; Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, 55281, Indonesia; Laboratory of Medicinal Chemistry, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, 55281, Indonesia


The efficacy of fulvestrant therapy for estrogen receptor positive (ER+) or luminal breast cancer therapy may decrease on account of chemoresistance, which contributes to tumor relapse and metastasis. Cinnamaldehyde has previously been shown to trigger apoptosis in MCF-7 cells, which are ER+ breast cancer cells. This study aimed to identify the targets and molecular mechanisms of cinnamaldehyde in overcoming fulvestrant-resistant breast cancer using a bioinformatics approach. The microarray data of fulvestrant-resistant and cinnamaldehyde-treated MCF-7 cells were obtained from GSE74391 and GSE85871, respectively, and a total of 310 differentially expressed genes (DEGs) were recovered from these databases. Gene Ontology analysis revealed several DEGs that participated in metabolic processes, responded to a stimulus, were located in the membrane and nucleus, and regulated the molecular functions of the protein and ion binding. Drug association analysis revealed the associations between these DEGs and protein kinase inhibitors. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that the DEGs regulated pathways for cancer, erbB, and MAPK signaling. Genetic alterations for each target gene ranged from 3 to 14% (CDK2, 3%; MDM2, 6%; KRAS, 7%; PIK3R1, 7%; CDH1, 8%; ESR1, 14%). Further investigation was conducted to examine the impact of genetic alterations on the signaling, resulting in BRCA-2012-RTK-RAS-PI(3)K-pathway. This study identified six possible targets of cinnamaldehyde in overcoming fulvestrant-resistant breast cancer, including CDK2, MDM2, KRAS, PIK3R1, CDH1, and ESR1. PI3K/Akt signaling is a possible target of cinnamaldehyde in overcoming fulvestrant-resistant breast cancer. Molecular docking study results showed that cinnamaldehyde could bind to several protein targets with specific properties and could also be considered to inhibit the activity of target proteins because of its protein-binding distance. Further investigations to verify the findings of this study are necessary. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.

Bioinformatics; Breast cancer; Cinnamaldehyde; Fulvestrant resistance; PI3K/Akt signaling


Network Modeling Analysis in Health Informatics and Bioinformatics

Publisher: Springer

Volume 10, Issue 1, Art No 30, Page – , Page Count

Journal Link: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85104586637&doi=10.1007%2fs13721-021-00303-9&partnerID=40&md5=74946ff0efad9c300b94a37efd090036

doi: 10.1007/s13721-021-00303-9

Issn: 21926662



Ahn, C.R., Park, J., Kim, J.E., Ahn, K.S., Kim, Y.W., Jeong, M., Kim, H.J., Baek, S., Cinnamaldehyde and hyperthermia co-treatment synergistically induces ROS-mediated apoptosis in ACHN renal cell carcinoma cells (2020) Biomedicines, 8 (9), p. E357; Ai, X., Xiang, L., Huang, Z., Zhou, S., Zhang, S., Zhang, T., Jiang, T., Overexpression of PIK3R1 promotes hepatocellular carcinoma progression (2018) Biol Res, 51 (1), p. 52; Almotlak, A.A., Farooqui, M., Siegfried, J.M., Inhibiting pathways predicted from a steroid hormone gene signature yields synergistic antitumor effects in NSCLC (2020) J Thorac Oncol, 15 (1), pp. 62-79; Alves, C.L., Elias, D., Lyng, M., Bak, M., Kirkegaard, T., Lykkesfeldt, A.E., Ditzel, H.J., High CDK6 protects cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant in estrogen receptor-positive metastatic breast cancer (2016) Clin Cancer Res, 22 (22), pp. 5514-5526; Alves, C.L., Elias, D., Lyng, M.B., Bak, M., Ditzel, H.J., SNAI2 upregulation is associated with an aggressive phenotype in fulvestrant-resistant breast cancer cells and is an indicator of poor response to endocrine therapy in estrogen receptor-positive metastatic breast cancer (2018) Breast Cancer Res, 20 (1), p. 60; Anjarsari, E.Y., Kristina, N., Larasati, Y.A., Putri, D.D.P., Meiyanto, E., Synergistic effect of cinnamon essential oil (Cinnamomum burmannii) and doxorubicin on T47D cells correlated with apoptosis induction (2013) Indones J Cancer Chemoprev, 4 (1), pp. 450-456; Browning, J.W.L., Rambo, T.M.E., McKay, B.C., Comparative genomic analysis of the 3′ UTR of human MDM2 identifies multiple transposable elements, an RLP24 pseudogene and a cluster of novel repeat sequences that arose during primate evolution (2020) Gene, 741, p. 144557; Caldon, C.E., Sergio, C.M., Kang, J., Muthukaruppan, A., Boersma, M.N., Stone, A., Barraclough, J., Musgrove, E.A., Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells (2012) Mol Cancer Ther, 11 (7), pp. 1488-1499; Cerami, E., Gao, J., Dogrusoz, U., Gross, B.E., Sumer, S.O., Aksoy, B.A., Jacobsen, A., Schultz, N., The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data (2012) Cancer Discov, 2 (5), pp. 401-404; Chang, W.-L., Cheng, F.-C., Wang, S.-P., Chou, S.-T., Shih, Y., Cinnamomum cassia essential oil and its major constituent cinnamaldehyde induced cell cycle arrest and apoptosis in human oral squamous cell carcinoma HSC-3 cells (2017) Environ Toxicol, 32 (2), pp. 456-468; Chen, L., Yang, L., Yao, L., Kuang, X.-Y., Zuo, W.-J., Li, S., Qiao, F., Shao, Z.-M., Characterization of PIK3CA and PIK3R1 somatic mutations in Chinese breast cancer patients (2018) Nat Commun, 9 (1), p. 1357; Chiang, Y.F., Chen, H.Y., Huang, K.C., Lin, P.H., Hsia, S.M., Dietary antioxidant trans-cinnamaldehyde reduced visfatin-induced breast cancer progression. Vivo and In Vitro Study (2019) Antioxidants (Basel), 8 (12), p. 625; Chin, C.H., Chen, S.H., Wu, H.H., Ho, C.W., Ko, M.T., Lin, C.Y., cytoHubba: identifying hub objects and sub-networks from complex interactome (2014) BMC Syst Biol, 8, p. S11; Ciruelos Gil, E.M., Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer (2014) Cancer Treat Rev, 40 (7), pp. 862-871; da Huang, W., Sherman, B.T., Lempicki, R.A., Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists (2009) Nucleic Acids Res, 37 (1), pp. 1-13; De Santo, I., McCartney, A., Migliaccio, I., Di Leo, A., Malorni, L., The emerging role of ESR1 mutations in luminal breast cancer as a prognostic and predictive biomarker of response to endocrine therapy (2019) Cancers (Basel), 11 (12), p. 1894; Dickson, A., Mapping the ligand binding landscape (2018) Biophys J, 115, pp. 1707-1719; Dolfi, S.C., Jäger, A.V., Medina, D.J., Haffty, B.G., Yang, J.M., Hirshfield, K.M., Fulvestrant treatment alters MDM2 protein turnover and sensitivity of human breast carcinoma cells to chemotherapeutic drugs (2014) Cancer Lett, 350 (1-2), pp. 52-60; Dong, K., Lei, Q., Guo, R., Wu, X., Zhang, Y., Cui, N., Shi, J.Y., Lu, T., Regulating intracellular ROS signal by a dual pH/reducing-responsive nanogels system promotes tumor cell apoptosis (2019) Int J Nanomed, 14, pp. 5713-5728; Du, G., Zhang, J., Luo, Z., Ma, F., Ma, L., Li, S., Joint imbalanced classification and feature selection for hospital readmissions (2020) Knowl-Based Syst, 200, p. 106020; Fang, S.-H., Rao, Y.K., Tzeng, Y.-M., Cytotoxic effect of trans-cinnamaldehyde from cinnamomum osmophloeum leaves on human cancer cell lines (2004) Int J Appl Sci Eng, 2 (2), pp. 136-147; Ferrer, I., Zugazagoitia, J., Herbertz, S., John, W., Paz-Ares, L., Schmid-Bindert, G., KRAS-Mutant non-small cell lung cancer: from biology to therapy (2018) Lung Cancer, 124, pp. 53-64; Gao, J., Aksoy, B.A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S.O., Sun, Y., Schultz, N., Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal (2013) Sci Signal, 6 (269), p. l1; Ghorbani, A., Jeddi-Tehrani, M., Saidpour, A., Safa, M., Bayat, A.A., Zand, H., PI3K/AKT and Mdm2 activation are associated with inhibitory effect of cAMP increasing agents on DNA damage-induced cell death in human pre-B NALM-6 cells (2015) Arch Biochem Biophys, 566, pp. 58-66; Gul, A., Leyland-Jones, B., Dey, N., De, P., A combination of the PI3K pathway inhibitor plus cell cycle pathway inhibitor to combat endocrine resistance in hormone receptor-positive breast cancer: a genomic algorithm-based treatment approach (2018) Am J Cancer Res, 8 (12), pp. 2359-2376; Han, L., Mei, J., Ma, J., Wang, F., Gu, Z., Li, J., Zhang, Z., Qin, Z., Cinnamaldehyde induces endogenous apoptosis of the prostate cancer-associated fibroblasts via interfering the Glutathione-associated mitochondria function (2020) Med Oncol, 37 (10), p. 91; He, W., Zhang, W., Zheng, Q., Wei, Z., Wang, Y., Hu, M., Ma, F., Luo, C., Cinnamaldehyde causes apoptosis of myeloid-derived suppressor cells through the activation of TLR4 (2019) Oncol Lett, 18 (3), pp. 2420-2426; Hermawan, A., Putri, H., Utomo, R.Y., Comprehensive bioinformatics study reveals targets and molecular mechanism of hesperetin in overcoming breast cancer chemoresistance (2020) Mol Divers, 24, pp. 933-947; Huang, T.-C., Fu, H.-Y., Ho, C.-T., Tan, D., Huang, Y.-T., Pan, M.-H., Induction of apoptosis by cinnamaldehyde from indigenous cinnamon Cinnamomum osmophloeum Kaneh through reactive oxygen species production, glutathione depletion, and caspase activation in human leukemia K562 cells (2007) Food Chem, 103 (2), pp. 434-443; Huang, X., Li, Z., Zhang, Q., Wang, W., Li, B., Wang, L., Xu, Z., Xu, Z., Circular RNA AKT3 upregulates PIK3R1 to enhance cisplatin resistance in gastric cancer via miR-198 suppression (2019) Mol Cancer, 18 (1), p. 71; Jeanes, A., Gottardi, C.J., Yap, A.S., Cadherins and cancer: how does cadherin dysfunction promote tumor progression? (2008) Oncogene, 27 (55), pp. 6920-6929; Jung, J.H., You, S., Oh, J.W., Yoon, J., Yeon, A., Shahid, M., Cho, E., Kim, J., Integrated proteomic and phosphoproteomic analyses of cisplatin-sensitive and resistant bladder cancer cells reveal CDK2 network as a key therapeutic target (2018) Cancer Lett, 437, pp. 1-12; Juric, D., Janku, F., Rodón, J., Burris, H.A., Mayer, I.A., Schuler, M., Seggewiss-Bernhardt, R., Rugo, H.S., Alpelisib plus fulvestrant in PIK3CA-altered and PIK3CA-wild-type estrogen receptor-positive advanced breast cancer: a phase 1b clinical trial (2019) JAMA Oncol, 5 (2); Ka, H., Park, H.-J., Jung, H.-J., Choi, J.-W., Cho, K.-S., Ha, J., Lee, K.-T., Cinnamaldehyde induces apoptosis by ROS-mediated mitochondrial permeability transition in human promyelocytic leukemia HL-60 cells (2003) Cancer Lett, 196 (2), pp. 143-152; Kim, M.J., Lee, S.J., Ryu, J.H., Kim, S.H., Kwon, I.C., Roberts, T.M., Combination of KRAS gene silencing and PI3K inhibition for ovarian cancer treatment (2020) J Control Release, 318, pp. 98-108; Kostrzewa, T., Przychodzen, P., Gorska-Ponikowska, M., Kuban-Jankowska, A., Curcumin and cinnamaldehyde as PTP1B inhibitors with antidiabetic and anticancer potential (2019) Anticancer Res, 39 (2), pp. 745-749; Koundouros, N., Poulogiannis, G., Phosphoinositide 3-kinase/Akt signaling and redox metabolism in cancer (2018) Front Oncol, 8, p. 160; Lal, N., White, B.S., Goussous, G., Pickles, O., Mason, M.J., Beggs, A.D., Taniere, P., Middleton, G.W., KRAS mutation and consensus molecular subtypes 2 and 3 are independently associated with reduced immune infiltration and reactivity in colorectal cancer (2018) Clin Cancer Res, 24 (1), pp. 224-233; Larasati, Y.A., Putri, D.P., Utomo, R.Y., Hermawan, A., Meiyanto, E., Combination of cisplatin and cinnamon essential oil inhibits HeLa cells proliferation through cell cycle arrest (2014) J Appl Pharm Sci, 4 (12), pp. 14-19; Lau, M.T., Klausen, C., Leung, P.C., E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression (2011) Oncogene, 30 (24), pp. 2753-2766; Lefebvre, C., Bachelot, T., Filleron, T., Pedrero, M., Campone, M., Soria, J.C., Massard, C., Andre, F., Mutational profile of metastatic breast cancers: a retrospective analysis (2016) PLoS Med, 13 (12); Li, J., Teng, Y., Liu, S., Wang, Z., Chen, Y., Zhang, Y., Xi, S., Zou, X., Cinnamaldehyde affects the biological behavior of human colorectal cancer cells and induces apoptosis via inhibition of the PI3K/Akt signaling pathway (2016) Oncol Rep, 35 (3), pp. 1501-1510; Li, X., Mak, V.C.Y., Zhou, Y., Wang, C., Wong, E.S.Y., Sharma, R., Lu, Y., Cheung, L.W.T., Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer (2019) Nat Commun, 10 (1), p. 716; Liu, P., Wang, Y., Li, X., Targeting the untargetable KRAS in cancer therapy (2019) Acta Pharm Sin B, 9 (5), pp. 871-879; Loi, S., Dushyanthen, S., Beavis, P.A., Salgado, R., Denkert, C., Savas, P., Combs, S., Estrada, M.V., RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors (2016) Clin Cancer Res, 22 (6), pp. 1499-1509; Lu, J., McEachern, D., Li, S., Ellis, M.J., Wang, S., Reactivation of p53 by MDM2 inhibitor MI-77301 for the treatment of endocrine-resistant breast cancer (2016) Mol Cancer Ther, 15 (12), pp. 2887-2893; Luo, J., Cantley, L.C., The negative regulation of phosphoinositide 3-kinase signaling by p85 and its implication in cancer (2005) Cell Cycle, 4 (10), pp. 1309-1312; Lv, C., Wu, X., Wang, X., Su, J., Zeng, H., Zhao, J., Lin, S., Zhang, W., The gene expression profiles in response to 102 traditional Chinese medicine (TCM) components: a general template for research on TCMs (2017) Sci Rep, 7 (1), p. 352; Lymperatou, D., Giannopoulou, E., Koutras, A.K., Kalofonos, H.P., The exposure of breast cancer cells to fulvestrant and tamoxifen modulates cell migration differently (2013) Biomed Res Int, 2013, p. 147514; Marino, M., Galluzzo, P., Ascenzi, P., Estrogen signaling multiple pathways to impact gene transcription (2006) Curr Genomics, 7 (8), pp. 497-508; McAndrew, N.P., Finn, R.S., Management of ER positive metastatic breast cancer (2020) Semin Oncol, S0093–7754 (20), pp. 30082-30088; Mei, J., Ma, J., Xu, Y., Wang, Y., Hu, M., Ma, F., Qin, Z., Tao, N., Cinnamaldehyde treatment of prostate cancer-associated fibroblasts prevents their inhibitory effect on T cells through toll-like receptor 4 (2020) Drug Des Dev Ther, 14, pp. 3363-3372; Meng, M., Geng, S., Du, Z., Yao, J., Zheng, Y., Li, Z., Zhang, Z., Du, G., Berberine and cinnamaldehyde together prevent lung carcinogenesis (2017) Oncotarget, 8 (44), pp. 76385-76397; Miller, T.W., Balko, J.M., Arteaga, C.L., Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer (2011) J Clin Oncol, 29 (33), pp. 4452-4461; Nathan, M.R., Schmid, P., A review of fulvestrant in breast cancer (2017) Oncol Ther, 5 (1), pp. 17-29; Ng, L.T., Wu, S.J., Antiproliferative activity of cinnamomum cassia constituents and effects of pifithrin-alpha on their apoptotic signaling pathways in Hep G2 cells (2011) Evid Based Complement Altern Med, 2011, p. 492148; Nishikawa, M., Reactive oxygen species in tumor metastasis (2008) Cancer Lett, 266 (1), pp. 53-59; Nunnery, S.E., Mayer, I.A., Targeting the PI3K/AKT/mTOR pathway in hormone-positive breast cancer (2020) Drugs; Okoh, V.O., Felty, Q., Parkash, J., Poppiti, R., Roy, D., Reactive oxygen species via redox signaling to PI3K/AKT pathway contribute to the malignant growth of 4-hydroxy estradiol-transformed mammary epithelial cells (2013) PLoS ONE, 8; Ortega, M.A., Fraile-Martínez, O., Asúnsolo, Á., Buján, J., García-Honduvilla, N., Coca, S., Signal transduction pathways in breast cancer: the important role of PI3K/Akt/mTOR (2020) J Oncol, 2020, p. 9258396; Cancer Profile Global 2020 (2020) Pan America Health Organization, , https://www.paho.org/hq/index.php?option=com_docman&view=download&category_slug=4-cancer-country-profiles-2020&alias=51561-global-cancer-profile-2020&Itemid=270&lang=fr; Pancholi, S., Leal, M.F., Ribas, R., Simigdala, N., Schuster, E., Chateau-Joubert, S., Zabaglo, L., Martin, L.A., Combination of mTORC1/2 inhibitor vistusertib plus fulvestrant in vitro and in vivo targets oestrogen receptor-positive endocrine-resistant breast cancer (2019) Breast Cancer Res, 21, p. 135; Park, J., Baek, S.H., Combination therapy with cinnamaldehyde and hyperthermia induces apoptosis of A549 non-small cell lung carcinoma cells via regulation of reactive oxygen species and mitogen-activated protein kinase family (2020) Int J Mol Sci, 21, p. 6229; Patra, S., Young, V., Llewellyn, L., Senapati, J.N., Mathew, J., BRAF, KRAS and PIK3CA mutation and sensitivity to trastuzumab in breast cancer cell line model (2017) Asian Pac J Cancer Prev, 18, pp. 2209-2213; Petrova, Y.I., Schecterson, L., Gumbiner, B.M., Roles for E-cadherin cell surface regulation in cancer (2016) Mol Biol Cell, 27 (21), pp. 3233-3244; Rani, A., Stebbing, J., Giamas, G., Murphy, J., Endocrine Resistance in Hormone Receptor Positive Breast Cancer-From Mechanism to Therapy (2019) Front Endocrinol (Lausanne), 10, p. 245; Reza, H.A., Anamika, W.J., Mostafa, M.G., Chowdhury, M.K., Uddin, M.A., MDM2 SNP 285 is associated with reduced lung cancer risk in bangladeshi population (2020) Mymensingh Med J, 29 (1), pp. 108-114; Shannon, P., Markiel, A., Ozier, O., Baliga, N.S., Wang, J.T., Ramage, D., Amin, N., Ideker, T., Cytoscape: a software environment for integrated models of biomolecular interaction networks (2003) Genome Res, 13 (11), pp. 2498-2504; Sharma, U., Sharma, A.K., Gupta, A., Kumar, R., Pandey, A.K., Pandey, A., Pharmacological activities of cinnamaldehyde and eugenol: antioxidant, cytotoxic and anti-leishmanial aspects (2017) Cell Mol Biol (Noisy le Grand), 63 (6), pp. 73-78; Shin, S.Y., Jung, H., Ahn, S., Hwang, D., Yoon, H., Hyun, J., Yong, Y., Lim, Y., Polyphenols bearing cinnamaldehyde scaffold showing cell growth inhibitory effects on the cisplatin-resistant A2780/Cis ovarian cancer cells (2014) Bioorg Med Chem, 22 (6), pp. 1809-1820; Simsek, S., Kursuncu, U., Kibis, E., AnisAbdellatif, M., Dag, A., A hybrid data mining approach for identifying the temporal effects of variables associated with breast cancer survival (2020) Expert Syst Appl, 139, p. 112863; Štefaniková, A., Klačanová, K., Pilchová, I., Hatok, J., Račay, P., Cyclin-dependent kinase 2 inhibitor SU9516 increases sensitivity of colorectal carcinoma cells Caco-2 but not HT29 to BH3 mimetic ABT-737 (2017) Gen Physiol Biophys, 36 (5), pp. 539-547; Swetzig, W.M., Wang, J., Das, G.M., Estrogen receptor alpha (ERα/ESR1) mediates the p53-independent overexpression of MDM4/MDMX and MDM2 in human breast cancer (2016) Oncotarget, 7 (13), pp. 16049-16069; Szklarczyk, D., Franceschini, A., Wyder, S., Forslund, K., Heller, D., Huerta-Cepas, J., Simonovic, M., von Mering, C., STRING v10: protein-protein interaction networks, integrated over the tree of life (2015) Nucleic Acids Res, 43 (Database issue), pp. D447-D452; Taniguchi, C.M., Winnay, J., Kondo, T., Bronson, R.T., Guimaraes, A.R., Alemán, J.O., Luo, J., Kahn, C.R., The phosphoinositide 3-kinase regulatory subunit p85alpha can exert tumor suppressor properties through negative regulation of growth factor signaling (2010) Cancer Res, 70 (13), pp. 5305-5315; Thorpe, L.M., Spangle, J.M., Ohlson, C.E., Cheng, H., Roberts, T.M., Cantley, L.C., Zhao, J.J., PI3K-p110α mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K-p85α (2017) Proc Natl Acad Sci USA, 114 (27), pp. 7095-7100; Tian, F., Yu, C.T., Ye, W.D., Wang, Q., Cinnamaldehyde induces cell apoptosis mediated by a novel circular RNA hsa_circ_0043256 in non-small cell lung cancer (2017) Biochem Biophys Res Commun, 493 (3), pp. 1260-1266; Wade, M., Li, Y.C., Wahl, G.M., MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) Nat Rev Cancer, 13 (2), pp. 83-96; Wang, B., Song, J., Structural basis for the ORC1-Cyclin A association (2019) Protein Sci, 28 (9), pp. 1727-1733; Wang, Y., Xie, B.H., Lin, W.H., Huang, Y.H., Ni, J.Y., Hu, J., Cui, W., Li, H.P., Amplification of SMYD3 promotes tumorigenicity and intrahepatic metastasis of hepatocellular carcinoma via upregulation of CDK2 and MMP2 (2019) Oncogene, 38 (25), pp. 4948-4961; Wang, J., Zhang, N., Peng, M., Hua, X., Huang, C., Tian, Z., Xie, Q., Huang, C., p85α inactivates MMP-2 and suppresses bladder cancer invasion by inhibiting MMP-14 transcription and TIMP-2 degradation (2019) Neoplasia, 21 (9), pp. 908-920; Wierød, L., Rosseland, C.M., Lindeman, B., Oksvold, M.P., Grøsvik, H., Skarpen, E., Huitfeldt, H.S., CDK2 regulation through PI3K and CDK4 is necessary for cell cycle progression of primary rat hepatocytes (2007) Cell Prolif, 40 (4), pp. 475-487; Wu, S.-J., Ng, L.-T., Lin, C.-C., Cinnamaldehyde-induced apoptosis in human PLC/PRF/5 cells through activation of the proapoptotic Bcl-2 family proteins and MAPK pathway (2005) Life Sci, 77 (8), pp. 938-951; Wu, C., Zhuang, Y., Jiang, S., Tian, F., Teng, Y., Chen, X., Zheng, P., Zou, X., Cinnamaldehyde induces apoptosis and reverses epithelial-mesenchymal transition through inhibition of Wnt/β-catenin pathway in non-small cell lung cancer (2017) J Biochem Cell Biol, 84, pp. 58-74; Wu, C.-E., Zhuang, Y.-W., Zhou, J.-Y., Liu, S.-L., Wang, R.-P., Shu, P., Cinnamaldehyde enhances apoptotic effect of oxaliplatin and reverses epithelial-mesenchymal transition and stemnness in hypoxic colorectal cancer cells (2019) Expe Cell Res, 383 (1), p. 111500; Xia, E., Sun, W., Mei, J., Xu, E., Wang, K., Qin, Y., Mining disease-symptom relation from massive biomedical literature and its application in severe disease diagnosis (2018) AMIA Annu Symp Proc, 2018, pp. 1118-1126; Xu, X.Z., Li, X.A., Luo, Y., Liu, J.F., Wu, H.W., Huang, G., MiR-9 promotes synovial sarcoma cell migration and invasion by directly targeting CDH1 (2019) Int J Biochem Cell Biol, 112, pp. 61-71; Yan, L., Song, F., Li, H., Li, Y., Li, J., He, Q.-Y., Zhang, D., Wang, S.-W., Submicron emulsion of cinnamaldehyde ameliorates bleomycin-induced idiopathic pulmonary fibrosis via inhibition of inflammation, oxidative stress and epithelial-mesenchymal transition (2018) Biomed Pharmacother, 102, pp. 765-771; Yang, G., Deng, Q., Fan, W., Zhang, Z., Xu, P., Tang, S., Wang, P., Yu, M., Cyclooxygenase-2 expression is positively associated with lymph node metastasis in nasopharyngeal carcinoma (2017) PLoS ONE, 12 (3); Yeh, W.L., Shioda, K., Coser, K.R., Rivizzigno, D., McSweeney, K.R., Shioda, T., Fulvestrant-induced cell death and proteasomal degradation of estrogen receptor alpha protein in MCF-7 cells require the CSK c-Src tyrosine kinase (2013) PLoS ONE, 8 (4); Yi, J.H., Do, I.-G., Jang, J., Kim, S.T., Kim, K.-M., Park, S.H., Park, J.O., Lee, J., Anti-tumor efficacy of fulvestrant in estrogen receptor positive gastric cancer (2014) Sci Rep, 4, p. 7592; Zhang, L.L., Liu, J., Lei, S., Zhang, J., Zhou, W., Yu, H.G., PTEN inhibits the invasion and metastasis of gastric cancer via downregulation of FAK expression (2014) Cell Signal, 26 (5), pp. 1011-1020; Zhang, W., Gao, J., Cheng, C., Zhang, M., Liu, W., Ma, X., Lei, W., Bai, G., Cinnamaldehyde enhances antimelanoma activity through covalently binding ENO1 and exhibits a promoting effect with dacarbazine (2020) Cancers (Basel), 12 (2), p. 311; Zhang, W., Gao, J., Shen, F., Ma, X., Wang, Z., Hou, X., Hao, E., Bai, G., Cinnamaldehyde changes the dynamic balance of glucose metabolism by targeting ENO1 (2020) Life Sci, 258, p. 118151

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