International Journal of Biomedical and Clinical Sciences
Articles Information
International Journal of Biomedical and Clinical Sciences, Vol.1, No.2, Nov. 2016, Pub. Date: Sep. 10, 2016
Characterization of Key Molecular Mechanisms and Biological Pathways Involved in Wortmannin Induced Breast Cancer MCF-7 Programmed Cell Death
Pages: 30-35 Views: 3367 Downloads: 925
[01] Rozina Akter, Department of Applied Biosciences, University of Arkansas at Little Rock, Little Rock, Arkansas, USA.
[02] Michael A. Gealt, Central Michigan University, Mount Pleasant, Michigan, USA.
[03] Maurice G. Kleve, Department of Biology, University of Arkansas at Little Rock, Little Rock, Arkansas, USA.
[04] Md. Zakir Hossain, Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise (BRITE), North Carolina Central University, Durham, North Carolina, USA.
The present study aimed to explore the molecular mechanisms and biological pathways involved in Wortmannin induced breast cancer MCF-7 programmed cell death. The direct cellular and molecular effect of Wtmn was investigated selectively on the MCF-7 cancer cell line. To study morphological effects phase contrast microscopy was used. The mitochondrial membrane potential and detection of caspase activity were investigated using fluorescent microscopy. Our morphological, molecular, and caspases expression indicated the intrinsic apoptosis pathways involved, and confirmed the role of Wtmn in these pathways. Our experimental results demonstrated that Wortmannin (Wtmn), an irreversible and selective PI3-K inhibitor, inhibits the proliferation of MCF-7 breast cancer cells, and facilitates their entry into apoptosis. Our data established the anti-cancer properties of Wtmn on MCF-7 breast cancer cells. These studies directed us towards elucidating the molecular mechanisms and biological pathways mainly involved in this process. This findings offer potential drug screening to search for novel inducers of apoptosis on MCF-7 cells, and could be used to design better drugs.
MCF-7, Wortmannin, Caspase, Mitochondrial Membrane Potential, and Apoptosis
[01] Li, Y., Zhang L., Li, K., Li, J., Xiang, R., Zhang, J., Li, H., Xu, Y., Wei, Y., Gao J., and Lin, P., and Wei, Y. 2015. ZNF32 inhibits autophagy through the mTOR pathway and protects MCF-7 cells from stimulus-induced cell death. Scientific Reports 5, Article number: 9288 (2015), doi: 10.1038/srep09288.
[02] Jia, T., Zhang, L., Duan, Y., Zhang, M., Wang, G., Zhang, J. and Zhao, Z., 2014. The differential susceptibilities of MCF-7 and MDA-MB-231 cells to the cytotoxic effects of curcumin are associated with the PI3K/Akt-SKP2-Cip/Kips pathway. Cancer Cell International. 14:126. DOI: 10.1186/s12935-014-0126-4.
[03] Wymann MP, Bulgarelli-Leva G, Zvelebil MJ. 1996. Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol Cell Biol.; 16(4): 1722-33.
[04] Schultz RM., Merriman RL. Andis SL. 1995. In vitro and in vivo antitumor activity of the phosphatidylinositol-3-kinase inhibitor, wortmannin. Anticancer Res; 15(4): 1135-9.
[05] Davol PA, Bizuneh A, Frackelton AR Jr. 1999. Wortmannin, a phosphoinositide 3kinase inhibitor, selectively enhances cytotoxicity of receptor-directed-toxin chimeras in vitro and in vivo. Anticancer Res.; 19(3A): 1705-13.
[06] Price BD Price BD, Youmell MB. 1996. The phosphatidylinositol 3-kinase inhibitor wortmannin sensitizes murine fibroblasts and human tumor cells to radiation and blocks induction of p53 following DNA damage. Cancer Res; 56(2): 246-50.
[07] Lemke LE, Paine-Murrieta GD, Taylor CW, Powis G. 1999. Wortmannin inhibits the growth of mammary tumors despite the existence of a novel wortmannin-insensitive phosphatidylinositol-3-kinase. Cancer Chemo ther Pharmacol; 44 (6): 491-7.
[08] Mattiasson G. 2004. Flow cytometric analysis of isolated liver mitochondria to detect changes relevant to cell death. Cytometry A; 60(2): 145-54.
[09] Hossain, M. Z, Khudhayer, W. J., Akter, R., Karabacak, T., and Kleve, M. G. 2016. Cytotoxic and anti-cancer effects of nickel nanowires against pancreatic cancer cells. Materials Research Society Proceedings Volume 1416-2012.
[10] Punj, V. and Chakrabarty, A. M. 2003. Redox proteins in mammalian cell death: an evolutionarily conserved function in mitochondria and prokaryotes. Cellular Microbiology; 5: 225–231.
[11] Akter R, Hossain MZ, Kleve MG, and Gealt MA. 2012. Wortmannin induces MCF-7 breast cancer cell death via the apoptotic pathway, involving chromatin condensation, generation of reactive oxygen species, and membrane blebbing. Breast Cancer: Targets and Therapy. 4: 103–113.
[12] Muhamad S., Lope Pihie A. H., Latif J., Rha C, and Sambandan T. G. 2011. Induction of apoptosis in MCF-7 via the Caspase pathway by longilactone from Eurycoma longifolia Jack. Research in Pharmaceutical Biotechnology; 3(1): 1–1.
[13] Waxman DJ, Schwartz PS. 2003. Harnessing apoptosis for improve anticancer gene therapy. Cancer Res; 63: 8563-8572.
[14] Jeong SY, Seol DW. 2008. The role of mitochondria in apoptosis. BMB Rep; 41(1): 1122.
[15] Abu Faddan N, Sayed D, Ghaleb F. 2011. T lymphocytes apoptosis and mitochondrial membrane potential in Down's syndrome. Fetal Pediatr Pathol. Egypt J Pediatr Allergy Immunol. 8(1): 35-40.
[16] Sun L, Chen T, Wang X, Chen Y, Wei X. 2011. Bufalin Induces Reactive Oxygen Species Dependent Bax Translocation and Apoptosis in ASTC-a-1 Cells. Evid Based Complement Alternat Med; 249-090.
[17] Lopez-Mediavillaa C., Orfaob A., Gonzaleza M., Medinaa JM. 1989. Identification by flowcytometry of two distinct rhodamine-123-stained mitochondrial populations in rat liver FEBS letter; 254 (1–2): 115–120.
[18] Shim HY, Park JH, Paik HD, Nah SY, Kim DS, Han YS. 2007. Acacetin-induced apoptosis of human breast cancer MCF-7 cells involves caspase cascade, mitochondriamediated death signaling and SAPK/JNK1/2-c-Jun activation. Mol Cells; 24(1): 95-104.
[19] Ding, W. X., Shen, H. M., and Ong, C. N. 2000. Critical role of reactive oxygen species and mitochondrial permeability transition in microcystin-induced rapid apoptosis in rat hepatocytes. Hepatology 32, 547−555.
[20] Schrivastava A., Tiwari M., Sinha RA., Kumar A., Balapure AK.. 2006. Molecular iodine induces caspase independent apoptosis in human breast carcinoma cells involving mitochondria-mediated pathway. J. Biol. Chem; 281: 19762−19771.
[21] Chan WH, Wu HJ, Shiao NH. 2007. Apoptotic signaling in methylglyoxal-treated human osteoblasts involves oxidative stress, c-Jun N-terminal kinase, caspase-3, and p21activated kinase 2. J Cell Biochem.; 100(4): 1056-69.
[22] Jänicke RU. 2009. MCF-7 breast carcinoma cells do not express caspase-3. Breast Cancer Research and Treatment; 117 (1): 219–221.
[23] Chua YL, Zhang D, Boelsterli U, Moore PK, Whiteman M, Armstrong JS. 2005. Oltipraz-induced phase 2 enzyme response conserved in cells lacking mitochondrial DNA. Biochem Biophys Res Commun. 337(1): 375-81.
[24] Armstrong JS, Steinauer KK, Hornung B, Irish JM, Lecane P, Birrell GW, Peehl DM, Knox SJ. 2002. Role of glutathione depletion and reactive oxygen species generation in apoptotic signaling in a human B lymphoma cell line. Cell Death Differ. 9(3): 252-63.
[25] Grivicich, I., Regner, A., da Rocha, A. B., Grass, L. B., Alves, P. A. 2005. Irinotecan/5fluorouracil combination induces alterations in mitochondrial membrane potential and caspases on colon cancer cell lines. Oncol. Res; 15, 385−392.
[26] Kallio, A., Zheng, A., Dahllund, J., Heiskanen, K. M., and Harkonen, P. 2005. Role of mitochondria in tamoxifen-induced rapid death of MCF-7 breast cancer cells. Apoptosis 10; 1395−1410.
[27] Roy A., Ganguly A, Dasgupta B., Das, Pal C, Jaisankar P. and Majumder HK. 2008. Mitochondria-Dependent Reactive Oxygen Species-Mediated Programmed Cell Death Induced by 3,3′-Diindolylmethane through Inhibition of F0F1-ATP Synthase in Unicellular Protozoan Parasite Leishmania donovani. Molecular Pharmacology 74(5): 1292-1307.
[28] Gottlieb RA. 2001. Mitochondria and apoptosis. Biol Signals Recept 10: 147-161.
[29] Mehta A and Shaha C. 2004. Apoptotic death in Leishmania donovani promastigotes in response to respiratory chain inhibition: complex II inhibition results in increased pentamidine cytotoxicity. J Biol Chem 279: 11798-11813.
[30] Hossain M. Z. and Kleve M. G. 2011. Nickel nanowires induced and reactive oxygen species mediated apoptosis in human pancreatic adenocarcinoma cells. International Journal of Nanomedicine, 6: 1475–1485.
[31] Shi Y-Q., Blattmann. H., Crompton NE. 2000 Wortmannin selectively enhances radiation-induced apoptosis in proliferative but not quiescent cells. International Journal of Radiation Oncology; 49 (2): 421-425.
[32] Wang X., Wu Q., Zhang L., Wu Y., Shu Y. 2010. Wortmannin induced apoptosis of leukemia cells by reducing PI3K/Akt. The Chinese-German Journal of Clinical Oncology; 9(12): 734–738.
[33] Seol JW, Lee YJ, Kang HS, Kim IS, Kim NS, Kwak YG, Kim TH, Seol DW and Park SY. 2005. Wortmannin elevates tumor necrosis factor-related apoptosis-inducing ligand sensitivity in LNCaP cells through down-regulation of IAP-2 protein. Exp Oncol; 27(2): 120-4.
[34] Wu Q, Chen Y, Guohui Cui, Cheng Y. 2009. Wortmannin inhibits K562 leukemic cells by regulating PI3k/Akt channel in vitro. Journal of Huazhong University of Science and Technology - Medical Sciences; 29: 451–456.
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