Abstract
Gastric cancer is one of the lethal causes of cancer-related deaths worldwide. The incidence and mortality rates of this disease is comparatively higher in China. In the current study, we evaluated the anticancer effects of Thymoquinone (TQ) against gastric cancer cells (MGC80-3 and SGC-7901) and normal noncancerous GES-1 cells and attempted to investigate the underlying mechanism. Our results indicated that TQ exhibited significant growth inhibitory effects on gastric cancer cells (MGC80-3 and SGC-7901). However, lower cytotoxicity was observed against normal GES-1 cells. Moreover, TQ could inhibit the colony formation potential of MGC80-3 and SGC-7901 cells in a dose-dependent manner. TQ also inhibited cell migration ability of the gastric cancer cells and down-regulated the expression of the mesenchymal genes such as N-cadherin, Vimentin, and TWIST. However, the epithelial markers such as E-cadherin and cytokeratin-19 were distinctly up-regulated in TQ-treated gastric cancer cells. Since PI3K/Akt/ mTOR plays an important role in progression and tumorigenesis, we also investigated the effect of TQ on PI3K/Akt/mTOR signalling pathway in gastric cancer cells. It was observed that TQ down-regulated the expression of some of the key proteins of this pathway. Taken together, we conclude that TQ may prove lead molecule for the treatment of gastric cancer.
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References
Abukhader MM 2013 Thymoquinone in the clinical treatment of cancer: fact or fiction? Pharmacogn. Rev. 7 117–120
Amin B and Hosseinzadeh H 2016 Black cumin (Nigella sativa) and its active constituent, thymoquinone: an overview on the analgesic and anti-inflammatory effects. Planta Med. 82 8–16
Balint K, Xiao M, Pinnix CC, Soma A, Veres I, Juhasz I, et al. 2005 Activation of Notch1 signalling is required for beta-catenin-mediated human primary melanoma progression. J. Clin. Invest. 115 3166–3176
Chen J, Guo J, Chen Z, Wang J, Liu M and Pang X 2016 Linifanib (ABT-869) Potentiates the efficacy of chemotherapeutic agents through the suppression of receptor tyrosine kinase-mediated AKT/mTOR signalling pathways in gastric cancer. Sci. Rep. 6 29382
Darakhshan S, Bidmeshki Pour A, Hosseinzadeh Colagar A and Sisakhtnezhad 2015 Thymoquinone and its therapeutic potentials. Pharmacol. Res. 95 138–158
Das A, Bhattacharya A, Chakrabarty S, Ganguli A and Chakrabarti G 2013 Smokeless tobacco extract (STE)-induced toxicity in mammalian cells is mediated by the disruption of cellular microtubule network: a key mechanism of cytotoxicity. PLoS ONE 8 e68224
Dergarabetian EM, Ghattass KI, El-Sitt SB, Al-Mismar RM, El-Baba CO, Itani WS, et al. 2013 Thymoquinone induces apoptosis in malignant T-cells via generation of ROS. Front. Biosci. 5 706–719
Gotoda T, Kusano C and Moriyasu F 2014 Future perspective of gastric cancer endotherapy. Ann. Transl. Med. 2 25
Hu B, El Hajj N, Sittler S, Lammert N, Barnes R and Meloni-Ehrig A 2012. Gastric cancer: Classification, histology and application of molecular pathology. J. Gastrointest. Oncol. 3 251–261
Hussain AR, Ahmed M, Ahmed S, Manogaran P, Platanias LC, Alvi SN, et al. 2011 Thymoquinone suppresses growth and induces apoptosis via generation of reactive oxygen species in primary effusion lymphoma. Free Radic. Biol. Med. 50 978–987
Isinger-Ekstrand A, Johansson J, Ohlsson M, Francis P, Staaf J and Jonsson M 2010 Genetic profiles of gastroesophageal cancer: combined analysis using expression array and tiling array–comparative genomic hybridization. Cancer Genet. Cytogenet. 200 120–126
Kai K, D’Costa S, Yoon BI, Brody AR, Sills RC and Kim Y 2010 Characterization of side population cells in human malignant mesothelioma cell lines. Lung Cancer 70 146–151
Kalluri R and Weinberg RA 2009 The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119 1420–1428
Kalluri R 2009 EMT: When epithelial cells decide to become mesenchymal-like cells. J. Clin. Invest. 119 1417–1419
Kawai T, Yanagizawa K, Naito S, Sugimoto H, Fukuzawa M and Gotoda T 2014 Evaluation of gastric cancer diagnosis using new ultrathin transnasal endoscopy with narrow-band imaging: preliminary study. J. Gastroenterol. Hepatol. 29 33–36
Khader M and Eckl PM 2014. Thymoquinone: an emerging natural drug with a wide range of medical applications. Iran J. Basic Med. Sci. 17 950–957
Larue L and Bellacosa A 2005 Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3’ kinase/AKT pathways. Oncogene 24 7443–7454
Li XJ, Xie HL, Lei SJ, Cao HQ, Meng TY and Hu YL 2012 Reduction of CAII expression in gastric cancer: correlation with invasion and metastasis. Chin. J. Can. Res. 24 196–200
Neiva KG, Zhang Z, Miyazawa M, Warner KA, Karl E and Nör JE 2009 Cross talk initiated by endothelial cells enhances migration and inhibits anoikis of squamous cell carcinoma cells through STAT3/Akt/ERK signalling. Neoplasia 11 583IN12–93IN14
Park JY, Ryu KW, Eom BW, Yoon HM, Kim SJ and Cho SJ 2014 Proposal of the surgical options for primary tumor control during sentinel node navigation surgery based on the discrepancy between preoperative and postoperative early gastric cancer diagnoses. Ann. Surg. Oncol. 21 1123–1129
Rajput S, Kumar BN, Sarkar S, Das S, Azab B, Santhekadur PK, et al. 2013 Targeted apoptotic effects of thymoquinone and tamoxifen on XIAP mediated Akt regulation in breast cancer. PLoS ONE 8 e61342
Riquelme I, Tapia O, Espinoza JA, Leal P, Buchegger K, Sandoval A, et al. 2016 The gene expression status of the PI3K/AKT/mTOR pathway in gastric cancer tissues and cell lines. Pathol. Oncol. Res. 22 797–805
Schneider-Stock R, Fakhoury IH, Zaki AM, El-Baba CO and Gali-Muhtasib HU 2014 Thymoquinone: fifty years of success in the battle against cancer models. Drug Discov. Today 19 18–30
Tanno B, Sesti F, Cesi V, Bossi G, Ferrari-Amorotti G, Bussolari R, et al. 2010. Expression of Slug is regulated by c-Myb and is required for invasion and bone marrow homing of cancer cells of different origin. J. Biol. Chem. 285 29434–29445
Woo CC, Hsu A, Kumar AP, Sethi G and Tan KH 2013 Thymoquinone inhibits tumor growth and induces apoptosis in a breast cancer xenograft mouse model: the role of p38 MAPK and ROS. PLoS ONE 8 e75356
Woo CC, Kumar AP, Sethi G and Tan KH 2012. Thymoquinone: potential cure for inflammatory disorders and cancer. Biochem. Pharmacol. 83 443–451
Wu A 2012 The 7th National Gastric Cancer Academic conference: focus on translational research in gastric cancer. Transl. Gastrointest. Cancer 1 277–283
Wu XJ, Yuan P, Li ZY, Bu ZD, Zhang LH, Wu AW, et al. 2013 Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves the survival of gastric cancer patients with ovarian metastasis and peritoneal dissemination. Tumor Biol. 34 463–469
Zhang CD, Chen SC, Feng ZF, Zhao ZM, Wang JN and Dai DQ 2013a Laparoscopic versus open gastrectomy for early gastric cancer in Asia: a meta-analysis. Surg. Laparosc. Endosc. Percutan. Tech. 23 365–377
Zhang CD, Zeng YJ, Li HW, Zhao ZM, Zhang JK and Dai DQ 2013bNeoadjuvant chemotherapy for nonmetastatic esophago-gastric adenocarcinomas: a systematic review and meta-analysis. Cancer Invest. 31 421–431
Zhao X, Li X and Yuan H 2013 microRNAs in gastric cancer invasion and metastasis. Front. Biosci. 18 803–810
Zhu WQ, Wang J, Guo XF, Liu Z and Dong WG 2016 Thymoquinone inhibits proliferation in gastric cancer via the STAT3 pathway in vivo and in vitro. World J. Gastroenterol. 22 4149–4159
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Communicated by SORAB DALAL.
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Feng, LM., Wang, XF. & Huang, QX. Thymoquinone induces cytotoxicity and reprogramming of EMT in gastric cancer cells by targeting PI3K/Akt/mTOR pathway. J Biosci 42, 547–554 (2017). https://doi.org/10.1007/s12038-017-9708-3
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DOI: https://doi.org/10.1007/s12038-017-9708-3