Abstract
Alpha-tocopheryl succinate (α-TS) is a vitamin-E derivative with potential antitumor properties. In this study, we have investigated the effect of α-TS on the morphology and motility of the A431 human epidermoid carcinoma cell line and HaCaT immortalized nontumorigenic human keratinocytes. Phase contrast and fluorescent microscopy, in vitro wound healing assay (scratch test), and scanning electron microscopy have been used. In both cell lines, alteration of cell shape, actin-cytoskeleton reorganization, cell-surface smoothing, disappearance of microvillae, and cell-motility inhibition have been shown. These effects are similar in both cell lines, but in the HaCaT cell line they occur after treatment with higher α-TS doses than for A431cells. Thus, we have demonstrated the selectivity of the effect of α-TS on tumor cells derived from human-skin stratified epithelia. The results of this work may be useful for further investigations focused on development of antitumor agents with selective action toward tumor cells.
Similar content being viewed by others
Abbreviations
- VES:
-
vitamin E succinate
References
Alexandrova, A.Y., Kopnin, P.B., Vasiliev, J.M., and Kopnin, B.P., ROS up-regulation mediates Ras-induced changes of cell morphology and motility, Exp. Cell Res., 2006, vol. 312, pp. 2066–2073.
Alleva, R., Benassi, M.S., Tomasetti, M., Gellert, N., Ponticelli, F., Borghi, B., Picci, P., and Neuzil, J., Alphatocopheryl succinate induces cytostasis and apoptosis in osteosarcoma cells: the role of E2F1, Biochem. Biophys. Res. Commun., 2005, vol. 331, pp. 1515–1521.
Dong, L.F., Swettenham, E., Eliasson, J., Wang, X.F., Gold, M., Medunic, Y., Stantic, M., Low, P., Prochazka, L., Witting, P.K., Turanek, J., Akporiaye, E.T., Ralph, S.J., and Neuzil, J., Vitamin E analogues inhibit angiogenesis by selective induction of apoptosis in proliferating endothelial cells: the role of oxidative stress, Cancer Res., 2007, vol. 67, pp. 11906–11913.
Douma, S., Van Laar, T., Zevenhoven, J., Meuwissen, R., Van Garderen, E., and Peeper, D.S., Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB, Nature, 2004, vol. 430, pp. 1034–1039.
Entschladen, F., Drell, IV, T., Lang, K., Joseph, J., and Zaenker, K., Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters, Lancet Oncol., 2004, vol. 5, pp. 254–258.
Giese, A., Bjerkvig, R., Berens, M.E., and Westphal, M., Cost of migration: invasion of malignant gliomas and implications for treatment, J. Clin. Oncol., 2003, vol. 21, pp. 1624–1636.
Gogvadze, V., Norberg, E., Orrenius, S., and Zhivotovsky, B., Involvement of Ca2+ and ROS in alphatocopheryl succinate-induced mitochondrial permeabilization, Int. J. Cancer, 2010, vol. 127, pp. 1823–1832.
Goldkorn, T. and Ding, T., The rise and fall of ceramide and 1,2-diacylglycerol (DAG): modulation by transforming growth factor-beta 1 (TGF beta 1) and by epidermal growth factor (EGF), Adv. Exp. Med. Biol., 1997, vol. 400A, pp. 461–472.
Goldkorn, T. and Mendelsohn, J., Transforming growth factor beta modulates phosphorylation of the epidermal growth factor receptor and proliferation of A431 cells, Cell Growth Differ., 1992, vol. 3, pp. 101–109.
Gu, X., Song, X., Dong, Y., Cai, H., Walters, E., Zhang, R., Pang, X., Xie, T., Guo, Y., Sridhar, R., and Califano, J.A., Vitamin E succinate induces ceramide-mediated apoptosis in head and neck squamous cell carcinoma in vitro and in vivo, Clin. Cancer Res., 2008, vol. 14, pp. 1840–1848.
Haga, A., Funasaka, T., Niinaka, Y., Raz, A., and Nagase, H., Autocrine motility factor signaling induces tumor apoptotic resistance by regulations Apaf-1 and Caspase-9 apoptosome expression, Int. J. Cancer, 2003, vol. 107, pp. 707–714.
Han, Y., Jiang, Q., Gao, H., Fan, J., Wang, Z., Zhong, F., Zheng, Y., Gong, Z., and Wang, C., The anti-apoptotic effect of polypeptide from Chlamys farreri (PCF) in UVBexposed HaCaT cells involves inhibition of iNOS and TGF-β1, Cell Biochem. Biophys., 2015, vol. 71, pp. 1105–1115.
Hu, W., Xu, R., Zhang, G., Jin, J., Szulc, Z.M., Bielawski, J., Hannun, Y.A., Obeid, L.M., and Mao, C., Golgi fragmentation is associated with ceramide-induced cellular effects, Mol. Biol. Cell., 2005, vol. 16, pp. 1555–1567.
Kanai, K., Kikuchi, E., Mikami, S., Suzuki, E., Uchida, Y., Kodaira, K., Miyajima, A., Ohigashi, T., Nakashima, J., and Oya, M., Vitamin E succinate induced apoptosis and enhanced chemosensitivity to paclitaxel in human bladder cancer cells in vitro and in vivo, Cancer Sci., 2010, vol. 101, pp. 216–223.
Kaneyuki, U., Ueda, S., Yamagishi, S., Kato, S., Fujimura, T., Shibata, R., Hayashida, A., Yoshimura, J., Kojiro, M., Oshima, K., and Okuda, S., Pitavastatin inhibits lysophosphatidic acid-induced proliferation and monocyte chemoattractant protein-1 expression in aortic smooth muscle cells by suppressing Rac-1-mediated reactive oxygen species generation, Vascul. Pharmacol., 2007, vol. 46, pp. 286–292.
Kim, H., Hwang, J.S., Woo, C.H., Kim, E.Y., Kim, T.H., Cho, K.J., Kim, J.H., Seo, J.M., and Lee, S.S., TNFalpha-induced up-regulation of intercellular adhesion molecule-1 is regulated by a Rac-ROS-dependent cascade in human airway epithelial cells, Exp. Mol. Med., 2008, vol. 40, pp. 167–175.
Kline, K., Yu, W., and Sanders, B.G., Vitamin E: mechanisms of action as tumor cell growth inhibitors, J. Nutr., 2001, vol. 131, pp. 161S–163S.
Kruspig, B., Zhivotovsky, B., and Gogvadze, V., Contrasting effects of A-tocopheryl succinate on cisplatin-and etoposide-induced apoptosis, Mitochondrion, 2013, vol. 13, pp. 533–538.
Kurokawa, K., Itoh, R.E., Yoshizaki, H., Nakamura, Y.O., and Matsuda, M., Coactivation of Rac1 and Cdc42 at lamellipodia and membrane ruffles induced by epidermal growth factor, Mol. Biol. Cell., 2004, vol. 15, pp. 1003–1010.
Lefranc, F., Brotchi, J., and Kiss, R., Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis, J. Clin. Oncol., 2005, vol. 23, pp. 2411–2422.
Neuzil, J., Svensson, I., Weber, T., Weber, C., and Brunk, U.T., Alpha-tocopheryl succinate-induced apoptosis in Jurkat T cells involves caspase-3 activation, and both lysosomal and mitochondrial destabilisation, FEBS Lett., 1999, vol. 445, pp. 295–300.
Neuzil, J., Swettenham, E., Wang, X.F., Dong, L.F., and Stapelberg, M., alpha Tocopheryl succinate inhibits angiogenesis by disrupting paracrine FGF2 signalling, FEBS Lett., 2007a, vol. 581, pp. 4611–4615.
Neuzil, J., Tomasetti, M., Zhao, Y., Dong, L.F., Birringer, M., Wang, X.F., Low, P., Wu, K., Salvatore, B.A., and Ralph, S.J., Vitamin E analogs, a novel group of “mitocans”, as anticancer agents: the importance of being redox-silent, Mol. Pharmacol., 2007b, vol. 71, pp. 1185–1199.
Ni, J., Chen, M., Zhang, Y., Li, R., Huang, J., and Yeh, S., Vitamin E succinate inhibits human prostate cancer cell growth via modulating cell cycle regulatory machinery, Biochem. Biophys. Res. Commun., 2003, vol. 300, pp. 357–363.
Pinilla, I., Piazuelo, E., Jiménez, P., Polo, V., Larrosa, J.M., Abecia, E., and Honrubia, F.M., Inhibitory effect of alpha tocopherol succinate on fibroblast wound healing, Arch. Soc. Esp. Oftalmol., 2000, vol. 75, pp. 383–388.
Prasad, K.N. and Edwards-Prasad, J., Effects of tocopherol (vitamin E) acid succinate on morphological alterations and growth inhibition in melanoma cells in culture, Cancer Res., 1982, vol. 42, pp. 550–555.
Prasad, K.N. and Edwards-Prasad, J., Vitamin E and cancer prevention: recent advances and future potentials, J. Am. Coll. Nutr., 1992, vol. 11, pp. 487–500.
Prochazka, L., Dong, L.F., Valis, K., Freeman, R., Ralph, S.J., Turanek, J., and Neuzil, J., Alpha-tocopheryl succinate causes mitochondrial permeabilization by preferential formation of Bak channels, Apoptosis, 2010, vol. 15, pp. 782–794.
Qadir, M.I., Parveen, A., and Ali, M., Cdc42: role in cancer management, Chem. Biol. Drug Des., 2015, vol. 86, pp. 432–439.
Rohlena, J., Dong, L.F., Kluckova, K., Zobalova, R., Goodwin, J., Tilly, D., Stursa, J., Pecinova, A., Philimonenko, A., Hozak, P., Banerjee, J., Ledvina, M., Sen, C.K., Houstek, J., Coster, M.J., and Neuzil, J., Mitochondrially targeted A-tocopheryl succinate is antiangiogenic: potential benefit against tumor angiogenesis but caution against wound healing, Antioxid. Redox Signal., 2011, vol. 15, pp. 2923–2935.
Savitskaya, M.A., Vildanova, M.S., Kisurina-Evgenieva, O.P., Smirnova, E.A., and Onischenko, G.E., Mitochondrial pathway of α-tocopheryl succinate-induced apoptosis in human epidermoid carcinoma A431 cells, Acta Naturae, 2012, vol. 4, pp. 88–94.
Scanlon, C.S., Van Tubergen, E.A., Inglehart, R.C., and D’Silva, N.J., Biomarkers of epithelial-mesenchymal transition in squamous cell carcinoma, J. Dent. Res., 2013, vol. 92, pp. 14–21.
Shiau, C.W., Huang, J.W., Wang, D.S., Weng, J.R., Yang, C.C., Lin, C.H., Li, C., and Chen, C.S., α-Tocopheryl succinate induces apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 function, J. Biol. Chem., 2006, vol. 281, pp. 11819–11825.
Singh, V.K., Brown, S.D., and Kao, T.-C., Alpha-tocopherol succinate protects mice from gamma-radiation by induction of granulocyte-colony stimulating factor, Int. J. Rad. Biol., 2010, vol. 86, pp. 12–21.
Singh, P.K., Wise, S.Y., Ducey, E.J., Fatanmi, O.O., Elliott, T.B., and Singh, V.K., α-Tocopherol succinate protects mice against radiation-induced gastrointestinal injury, Radiat. Res., 2012, vol. 177, pp. 133–145.
Sporn, M.B., The war on cancer, Lancet, 1996, vol. 347, pp. 1377–1381.
Tomasetti, M., Strafella, E., Staffolani, S., Santarelli, L., Neuzil, J., and Guerrieri, R., Alpha-tocopheryl succinate promotes selective cell death induced by vitamin K3 in combination with ascorbate, Br. J. Cancer, 2010, vol. 102, pp. 1224–1234.
Turley, J.M, Sanders, B.G, and Kline, K., RRR-alphatocopheryl succinate modulation of human promyelocytic leukemia (HL-60) cell proliferation and differentiation, Nutr. Cancer, 1992, vol. 18, pp. 201–213.
Wang, D., Chuang, H.C., Weng, S.C., Huang, P.H., Hsieh, H.Y., Kulp, S.K., and Chen, C.S., Alpha-tocopheryl succinate as a scaffold to develop potent inhibitors of breast cancer cell adhesion, J. Med. Chem., 2009, vol. 52, pp. 5642–5648.
Yamamoto, S., Tamai, H., Ishisaka, R., Kanno, T., Arita, K., Kobuchi, H., and Utsumi, K., Mechanism of alpha-tocopheryl succinate-induced apoptosis of promyelocytic leukemia cells, Free Radic., 2000, vol. 33, pp. 407–418.
Yarrow, J.C., Perlman, Z.E., Westwood, N.J., and Mitchison, T.J., A high-throughput cell migration assay using scratch wound healing, a comparison of image-based readout methods, BMC Biotechnol., 2004, vol. 4, p.21.
You, H., Yu, W., Sanders, B.G, and Kline, K., RRR-alphatocopheryl succinate induces MDA-MB-435 and MCF-7 human breast cancer cells to undergo differentiation, Cell Growth Differ., 2001, vol. 12, pp. 471–480.
You, H., Yu, W., Munoz-Medellin, D., Brown, P.H., Sanders, B.G., and Kline, K., Role of extracellular signal-regulated kinase pathway in RRR-alpha-tocopheryl succinateinduced differentiation of human MDA-MB-435 breast cancer cells, Mol. Carcinog., 2002, vol. 33, pp. 228–236.
Yu, W., Heim, K., Qian, M., Simmons-Menchaca, M., Sanders, B.G., and Kline, K., Evidence for role of transforming growth factor-beta in RRR-alpha-tocopheryl succinate-induced apoptosis of human MDA-MB-435 breast cancer cells, Nutr. Cancer, 1997, vol. 27, pp. 267–278.
Yu, W., Sanders, B.G, and Kline, K., RRR-alpha-tocopheryl succinate induction of DNA synthesis arrest of human MDA-MB-435 cells involves TGF-beta-independent activation of P21Waf1/Cip1, Nutr. Cancer, 2002, vol. 43, pp. 227–236.
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text © M.A. Savitskaya, G.E. Onischcenko, 2017, published in Tsitologiya, 2017, Vol. 59, No. 12, pp. 826–835.
Rights and permissions
About this article
Cite this article
Savitskaya, M.A., Onischcenko, G.E. Alpha-Tocopheryl Succinate Selectively Affects the Morphology and Motility of Normal and Tumor Epithelial Cells. Cell Tiss. Biol. 12, 102–111 (2018). https://doi.org/10.1134/S1990519X18020104
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S1990519X18020104