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Involvement of melastatin type transient receptor potential 7 channels in ginsenoside Rd-induced apoptosis in gastric and breast cancer cells

  • Kim, Byung Joo (Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University)
  • Received : 2012.09.21
  • Accepted : 2012.12.05
  • Published : 2013.04.15

Abstract

Ginsenoside, one of the active ingredients of Panax ginseng, has a variety of physiologic and pharmacologic effects. The purpose of this study was to explore the effects of ginsenoside Rd (G-Rd) on melastatin type transient receptor potential 7 (TRPM7) channels with respect to the proliferation and survival of AGS and MCF-7 cells (a gastric and a breast cancer cell line, respectively). AGS and MCF-7 cells were treated with different concentrations of G-Rd, and caspase-3 activities, mitochondrial depolarizations, and sub-G1 fractions were analyzed to determine if cell death occurred by apoptosis. In addition, human embryonic kidney (HEK) 293 cells overexpressing TRPM7 channels were used to confirm the role of TRPM7 channels. G-Rd inhibited the proliferation and survival of AGS and MCF-7 cells and enhanced caspase-3 activity, mitochondrial depolarization, and sub-G1 populations. In addition, G-Rd inhibited TRPM7-like currents in AGS and MCF-7 cells and in TRPM7 channel overexpressing HEK 293 cells, as determined by whole cell voltage-clamp recordings. Furthermore, TRPM7 overexpression in HEK 293 cells promoted G-Rd induced cell death. These findings suggest that G-Rd inhibits the proliferation and survival of gastric and breast cancer cells by inhibiting TRPM7 channel activity.

Keywords

References

  1. Kim HS, Parajuli SP, Yeum CH, Park JS, Jeong HS, So I, Kim KW, Jun JY, Choi S. Effects of ginseng total saponins on pacemaker currents of interstitial cells of Cajal from the small intestine of mice. Biol Pharm Bull 2007;30:2037-2042. https://doi.org/10.1248/bpb.30.2037
  2. Kim BJ, Park EJ, Lee JH, Jeon JH, Kim SJ, So I. Suppression of transient receptor potential melastatin 7 channel induces cell death in gastric cancer. Cancer Sci 2008;99:2502-2509. https://doi.org/10.1111/j.1349-7006.2008.00982.x
  3. Guilbert A, Gautier M, Dhennin-Duthille I, Haren N, Sevestre H, Ouadid-Ahidouch H. Evidence that TRPM7 is required for breast cancer cell proliferation. Am J Physiol Cell Physiol 2009;297:C493-C502. https://doi.org/10.1152/ajpcell.00624.2008
  4. Clapham DE. TRP channels as cellular sensors. Nature 2003;426:517-524. https://doi.org/10.1038/nature02196
  5. Nadler MJ, Hermosura MC, Inabe K, Perraud AL, Zhu Q, Stokes AJ, Kurosaki T, Kinet JP, Penner R, Scharenberg AM et al. LTRPC7 is a Mg.ATP-regulated divalent cation channel required for cell viability. Nature 2001;411:590-595. https://doi.org/10.1038/35079092
  6. Runnels LW, Yue L, Clapham DE. TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science 2001;291:1043-1047. https://doi.org/10.1126/science.1058519
  7. Jiang J, Li MH, Inoue K, Chu XP, Seeds J, Xiong ZG. Transient receptor potential melastatin 7-like current in human head and neck carcinoma cells: role in cell proliferation. Cancer Res 2007;67:10929-10938. https://doi.org/10.1158/0008-5472.CAN-07-1121
  8. Jin J, Desai BN, Navarro B, Donovan A, Andrews NC, Clapham DE. Deletion of Trpm7 disrupts embryonic development and thymopoiesis without altering Mg2+homeostasis. Science 2008;322:756-760. https://doi.org/10.1126/science.1163493
  9. Schmitz C, Perraud AL, Johnson CO, Inabe K, Smith MK, Penner R, Kurosaki T, Fleig A, Scharenberg AM. Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7. Cell 2003;114:191-200. https://doi.org/10.1016/S0092-8674(03)00556-7
  10. Kim BJ, Nah SY, Jeon JH, So I, Kim SJ. Transient receptor potential melastatin 7 channels are involved in ginsenoside Rg3-induced apoptosis in gastric cancer cells. Basic Clin Pharmacol Toxicol 2011;109:233-239. https://doi.org/10.1111/j.1742-7843.2011.00706.x
  11. Han S, Kim JS, Jung BK, Han SE, Nam JH, Kwon YK, Nah SY, Kim BJ. Effects of ginsenoside on pacemaker potentials of cultured interstitial cells of Cajal clusters from the small intestine of mice. Mol Cells 2012;33:243-249. https://doi.org/10.1007/s10059-012-2204-6
  12. Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 1991;139:271-279. https://doi.org/10.1016/0022-1759(91)90198-O
  13. Wang BJ, Won SJ, Yu ZR, Su CL. Free radical scavenging and apoptotic effects of Cordyceps sinensis fractionated by supercritical carbon dioxide. Food Chem Toxicol 2005;43:543-552. https://doi.org/10.1016/j.fct.2004.12.008
  14. Hotz MA, Gong J, Traganos F, Darzynkiewicz Z. Flow cytometric detection of apoptosis: comparison of the assays of in situ DNA degradation and chromatin changes. Cytometry 1994;15:237-244. https://doi.org/10.1002/cyto.990150309
  15. Vermes I, Haanen C, Reutelingsperger C. Flow cytometry of apoptotic cell death. J Immunol Methods 2000;243:167-190. https://doi.org/10.1016/S0022-1759(00)00233-7
  16. Fleig A, Penner R. Emerging roles of TRPM channels. Novartis Found Symp 2004;258:248-258. https://doi.org/10.1002/0470862580.ch18
  17. Harteneck C, Plant TD, Schultz G. From worm to man: three subfamilies of TRP channels. Trends Neurosci 2000;23:159-166. https://doi.org/10.1016/S0166-2236(99)01532-5
  18. Montell C. Physiology, phylogeny, and functions of the TRP superfamily of cation channels. Sci STKE 2001;2001:re1.
  19. Monteilh-Zoller MK, Hermosura MC, Nadler MJ, Scharenberg AM, Penner R, Fleig A. TRPM7 provides an ion channel mechanism for cellular entry of trace metal ions. J Gen Physiol 2003;121:49-60. https://doi.org/10.1085/jgp.20028740
  20. Minke B, Cook B. TRP channel proteins and signal transduction. Physiol Rev 2002;82:429-472. https://doi.org/10.1152/physrev.00001.2002
  21. Hanano T, Hara Y, Shi J, Morita H, Umebayashi C, Mori E, Sumimoto H, Ito Y, Mori Y, Inoue R. Involvement of TRPM7 in cell growth as a spontaneously activated Ca2+ entry pathway in human retinoblastoma cells. J Pharmacol Sci 2004;95:403-419. https://doi.org/10.1254/jphs.FP0040273
  22. He Y, Yao G, Savoia C, Touyz RM. Transient receptor potential melastatin 7 ion channels regulate magnesium homeostasis in vascular smooth muscle cells: role of angiotensin II. Circ Res 2005;96:207-215. https://doi.org/10.1161/01.RES.0000152967.88472.3e
  23. Aarts M, Iihara K, Wei WL, Xiong ZG, Arundine M, Cerwinski W, MacDonald JF, Tymianski M. A key role for TRPM7 channels in anoxic neuronal death. Cell 2003;115:863-877. https://doi.org/10.1016/S0092-8674(03)01017-1
  24. Krapivinsky G, Mochida S, Krapivinsky L, Cibulsky SM, Clapham DE. The TRPM7 ion channel functions in cholinergic synaptic vesicles and affects transmitter release. Neuron 2006;52:485-496. https://doi.org/10.1016/j.neuron.2006.09.033
  25. Su D, May JM, Koury MJ, Asard H. Human erythrocyte membranes contain a cytochrome b561 that may be involved in extracellular ascorbate recycling. J Biol Chem 2006;281:39852-39859. https://doi.org/10.1074/jbc.M606543200
  26. Kim BJ, Lim HH, Yang DK, Jun JY, Chang IY, Park CS, So I, Stanfield PR, Kim KW. Melastatin-type transient receptor potential channel 7 is required for intestinal pacemaking activity. Gastroenterology 2005;129:1504-1517. https://doi.org/10.1053/j.gastro.2005.08.016
  27. Wykes RC, Lee M, Duffy SM, Yang W, Seward EP, Bradding P. Functional transient receptor potential melastatin 7 channels are critical for human mast cell survival. J Immunol 2007;179:4045-4052. https://doi.org/10.4049/jimmunol.179.6.4045
  28. Abed E, Moreau R. Importance of melastatin-like transient receptor potential 7 and cations (magnesium, calcium) in human osteoblast-like cell proliferation. Cell Prolif 2007;40:849-865. https://doi.org/10.1111/j.1365-2184.2007.00476.x
  29. Hong H, Cui CH, Kim JK, Jin FX, Kim SC, Im WT. Enzymatic biotransformation of ginsenoside Rb1 and gypenoside XVII into ginsenosides Rd and F2 by recombinant ${\beta}$-glucosidase from Flavobacterium johnsoniae. J Ginseng Res 2012;36:418-424. https://doi.org/10.5142/jgr.2012.36.4.418
  30. Quan LH, Piao JY, Min JW, Kim HB, Kim SR, Yang DU, Yang DC. Biotransformation of ginsenoside Rb1 to prosapogenins, gypenoside XVII, ginsenoside Rd, ginsenoside F2, and compound K by Leuconostoc mesenteroides DC102. J Ginseng Res 2011;35:344-351. https://doi.org/10.5142/jgr.2011.35.3.344
  31. Sun HS, Jackson MF, Martin LJ, Jansen K, Teves L, Cui H, Kiyonaka S, Mori Y, Jones M, Forder JP et al. Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia. Nat Neurosci 2009;12:1300-1307. https://doi.org/10.1038/nn.2395
  32. Ye R, Li N, Han J, Kong X, Cao R, Rao Z, Zhao G. Neuroprotective effects of ginsenoside Rd against oxygen-glucose deprivation in cultured hippocampal neurons. Neurosci Res 2009;64:306-310. https://doi.org/10.1016/j.neures.2009.03.016
  33. Li N, Liu B, Dluzen DE, Jin Y. Protective effects of ginsenoside Rg2 against glutamate-induced neurotoxicity in PC12 cells. J Ethnopharmacol 2007;111:458-463. https://doi.org/10.1016/j.jep.2006.12.015
  34. Wu J, Jeong HK, Bulin SE, Kwon SW, Park JH, Bezprozvanny I. Ginsenosides protect striatal neurons in a cellular model of Huntington's disease. J Neurosci Res 2009;87:1904-1912. https://doi.org/10.1002/jnr.22017
  35. Ye R, Zhang X, Kong X, Han J, Yang Q, Zhang Y, Chen Y, Li P, Liu J, Shi M et al. Ginsenoside Rd attenuates mitochondrial dysfunction and sequential apoptosis after transient focal ischemia. Neuroscience 2011;178:169-180. https://doi.org/10.1016/j.neuroscience.2011.01.007
  36. Ye R, Yang Q, Kong X, Han J, Zhang X, Zhang Y, Li P, Liu J, Shi M, Xiong L, et al. Ginsenoside Rd attenuates early oxidative damage and sequential inflammatory response after transient focal ischemia in rats. Neurochem Int 2011;58:391-398. https://doi.org/10.1016/j.neuint.2010.12.015
  37. Liu X, Xia J, Wang L, Song Y, Yang J, Yan Y, Ren H, Zhao G. Efficacy and safety of ginsenoside-Rd for acute ischaemic stroke: a randomized, double-blind, placebo-controlled, phase II multicenter trial. Eur J Neurol 2009;16:569-575. https://doi.org/10.1111/j.1468-1331.2009.02534.x
  38. Zhang Y, Zhou L, Zhang X, Bai J, Shi M, Zhao G. Ginsenoside-Rd attenuates TRPM7 and ASIC1a but promotes ASIC2a expression in rats after focal cerebral ischemia. Neurol Sci 2012;33:1125-1131. https://doi.org/10.1007/s10072-011-0916-6
  39. Hao M, Wang W, Zhao Y, Zhang R, Wang H. Pharma-cokinetics and tissue distribution of 25-hydroxyprotopanaxadiol, an anti-cancer compound isolated from Panax ginseng, in athymic mice bearing xenografts of human pancreatic tumors. Eur J Drug Metab Pharmacokinet 2011;35:109-113. https://doi.org/10.1007/s13318-010-0022-9
  40. Li B, Zhao J, Wang CZ, Searle J, He TC, Yuan CS, Du W. Ginsenoside Rh2 induces apoptosis and paraptosis-like cell death in colorectal cancer cells through activation of p53. Cancer Lett 2011;301:185-192. https://doi.org/10.1016/j.canlet.2010.11.015
  41. He BC, Gao JL, Luo X, Luo J, Shen J, Wang L, Zhou Q, Wang YT, Luu HH, Haydon RC et al. Ginsenoside Rg3 inhibits colorectal tumor growth through the down-regulation of Wnt/b-catenin signaling. Int J Oncol 2011;38:437-445.

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