Eugenol and capsaicin exhibit anti-metastatic activity via modulating TGF-β signaling in gastric carcinoma.

The transforming growth factor-β (TGF-β) signaling is considered to be a key player in gastric cancer metastasis, and the inhibition of the TGF-β/SMAD4 signaling pathway may be a novel strategy for therapeutic interventions in cancer. Here, the anti-metastatic activity of two phytochemicals, eugenol and capsaicin, has been studied, and their potential to antagonize TGF-β has been investigated in gastric cancer cells. Both the phytochemicals exhibited anti-metastatic activity by inhibiting the TGF-β signaling pathway independent of P21 or P53, with capsaicin proving to be more potent than eugenol. However, unlike eugenol, the inhibitory effect of capsaicin on the TGF-β signaling pathway and metastasis was found to be dependent on SMAD4, which was validated in SMAD4-knocked down AGS cell and SMAD4-null SW620 cell line. Furthermore, the use of recombinant TGF-β and TGF-β receptor inhibitor LY2109761 confirmed that the anti-metastatic activity of eugenol is partially and that of capsaicin is principally mediated through the TGF-β signaling pathway. Identifying phytochemicals with the potential to inhibit cancer metastasis by targeting the TGF-β signaling pathway has immense scope for developing a therapeutic strategy against cancer metastasis.

[1]  Pablo Arbeláez,et al.  An image J plugin for the high throughput image analysis of in vitro scratch wound healing assays , 2020, bioRxiv.

[2]  P. ten Dijke,et al.  A Perspective on the Development of TGF-β Inhibitors for Cancer Treatment , 2019, Biomolecules.

[3]  D. Mandal,et al.  The inhibition of hypoxia-induced angiogenesis and metastasis by cinnamaldehyde is mediated by decreasing HIF-1α protein synthesis via PI3K/Akt pathway. , 2019, BioFactors.

[4]  A. Turtoi,et al.  High stromal transforming growth factor β–induced expression is a novel marker of progression and poor prognosis in gastric cancer , 2018, Journal of surgical oncology.

[5]  D. Jiang,et al.  Capsaicin inhibits proliferation and induces apoptosis in osteosarcoma cell lines via the mitogen-activated protein kinase pathway , 2017, Oncology reports.

[6]  E. Oki,et al.  Activation of Transforming Growth Factor Beta 1 Signaling in Gastric Cancer-associated Fibroblasts Increases Their Motility, via Expression of Rhomboid 5 Homolog 2, and Ability to Induce Invasiveness of Gastric Cancer Cells. , 2017, Gastroenterology.

[7]  Abhijit Mitra,et al.  Prediction of Anti-Alzheimer's Activity of Flavonoids Targeting Acetylcholinesterase in silico. , 2017, Phytochemical analysis : PCA.

[8]  R. Akhurst.  Targeting TGF-β Signaling for Therapeutic Gain. , 2017, Cold Spring Harbor perspectives in biology.

[9]  Hyung Gyun Kim,et al.  Capsaicin Inhibits Dimethylnitrosamine-Induced Hepatic Fibrosis by Inhibiting the TGF-β1/Smad Pathway via Peroxisome Proliferator-Activated Receptor Gamma Activation. , 2017, Journal of agricultural and food chemistry.

[10]  D. Mandal,et al.  Induction of Apoptosis by Eugenol and Capsaicin in Human Gastric Cancer AGS Cells--Elucidating the Role of p53. , 2015, Asian Pacific journal of cancer prevention : APJCP.

[11]  S. Srivastava,et al.  Modulation of signal transduction pathways by natural compounds in cancer. , 2015, Chinese journal of natural medicines.

[12]  Lei Zhou,et al.  Mutant p53 Promotes Tumor Cell Malignancy by Both Positive and Negative Regulation of the Transforming Growth Factor β (TGF-β) Pathway* , 2015, The Journal of Biological Chemistry.

[13]  Yongbing Chen,et al.  TGF-β-activated SMAD3/4 complex transcriptionally upregulates N-cadherin expression in non-small cell lung cancer. , 2015, Lung cancer.

[14]  L. Carcas.  Gastric cancer review , 2014, Journal of carcinogenesis.

[15]  Jun Peng,et al.  Baicalein inhibits migration and invasion of gastric cancer cells through suppression of the TGF-β signaling pathway. , 2014, Molecular medicine reports.

[16]  I. Han,et al.  Capsaicin suppresses the migration of cholangiocarcinoma cells by down-regulating matrix metalloproteinase-9 expression via the AMPK–NF-κB signaling pathway , 2014, Clinical & Experimental Metastasis.

[17]  O. Shaker,et al.  Targeting Transforming Growth Factor-β (TGF-β) in Cancer and Non-Neoplastic Diseases , 2014 .

[18]  M. Washington,et al.  Loss of Smad4 in colorectal cancer induces resistance to 5-fluorouracil through activating Akt pathway , 2014, British Journal of Cancer.

[19]  Linwei Wang,et al.  High expression of transform growth factor beta 1 in gastric cancer confers worse outcome: results of a cohort study on 184 patients. , 2014, Hepato-gastroenterology.

[20]  Yanhong Zhang,et al.  PUMA Cooperates with p21 to Regulate Mammary Epithelial Morphogenesis and Epithelial-To-Mesenchymal Transition , 2013, PloS one.

[21]  Moon‐Moo Kim,et al.  Eugenol with antioxidant activity inhibits MMP-9 related to metastasis in human fibrosarcoma cells. , 2013, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[22]  Lili Ma,et al.  Transforming Growth Factor-β1 and -β2 in Gastric Precancer and Cancer and Roles in Tumor-Cell Interactions with Peripheral Blood Mononuclear Cells In Vitro , 2013, PloS one.

[23]  J. Yang,et al.  Low-concentration capsaicin promotes colorectal cancer metastasis by triggering ROS production and modulating Akt/mTOR and STAT-3 pathways. , 2013, Neoplasma.

[24]  H. Lemos,et al.  Anti-arthritic effect of eugenol on collagen-induced arthritis experimental model. , 2012, Biological & pharmaceutical bulletin.

[25]  R. Akhurst,et al.  Complexities of TGF-β Targeted Cancer Therapy , 2012, International journal of biological sciences.

[26]  G. Inman,et al.  Crosstalk between p53 and TGF-β Signalling , 2012, Journal of signal transduction.

[27]  Hyung Gyun Kim,et al.  Suppression of EGF-induced tumor cell migration and matrix metalloproteinase-9 expression by capsaicin via the inhibition of EGFR-mediated FAK/Akt, PKC/Raf/ERK, p38 MAPK, and AP-1 signaling. , 2011, Molecular nutrition & food research.

[28]  Jin-Rong Zhou,et al.  Smad4 inactivation promotes malignancy and drug resistance of colon cancer. , 2011, Cancer research.

[29]  R. S. Murugan,et al.  Eugenol induces apoptosis and inhibits invasion and angiogenesis in a rat model of gastric carcinogenesis induced by MNNG. , 2010, Life sciences.

[30]  Y. Liu,et al.  TGF-beta promotes invasion and metastasis of gastric cancer cells by increasing fascin1 expression via ERK and JNK signal pathways. , 2009, Acta biochimica et biophysica Sinica.

[31]  R. Crystal,et al.  A SNAIL1–SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial–mesenchymal transition , 2009, Nature Cell Biology.

[32]  E. Horváthová,et al.  Investigation of anti-oxidative, cytotoxic, DNA-damaging and DNA-protective effects of plant volatiles eugenol and borneol in human-derived HepG2, Caco-2 and VH10 cell lines. , 2009, Mutation research.

[33]  Makio Kobayashi,et al.  Examination of transforming growth factor beta1 expression in the serum and tumor tissue of gastric cancer. , 2009, International surgery.

[34]  David Padua,et al.  Roles of TGFβ in metastasis , 2009, Cell Research.

[35]  O. Kim,et al.  Inhibitory effect of capsaicin on B16-F10 melanoma cell migration via the phosphatidylinositol 3-kinase/Akt/Rac1 signal pathway , 2008, Experimental & Molecular Medicine.

[36]  M. Jinnin,et al.  Characterization of SIS3, a Novel Specific Inhibitor of Smad3, and Its Effect on Transforming Growth Factor-β1-Induced Extracellular Matrix Expression , 2006, Molecular Pharmacology.

[37]  P. Seth,et al.  Targeting TGF beta signaling for cancer therapy , 2005, Cancer biology & therapy.

[38]  S. Dupont,et al.  Links between Tumor Suppressors p53 Is Required for TGF-β Gene Responses by Cooperating with Smads , 2003, Cell.

[39]  B. Qin,et al.  Crystal structure of a transcriptionally active Smad4 fragment. , 1999, Structure.

[40]  Takeshi Imamura,et al.  TGF‐β receptor‐mediated signalling through Smad2, Smad3 and Smad4 , 1997 .