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The Effects of ASMase Mediated Endothelial Cell Apoptosis in Multiple Hypofractionated Irradiations in CT26 Tumor Bearing Mice

  • Zhu, Hong (Department of Medical Oncology, West China Hospital, Sichuan University) ;
  • Deng, Kai (Department of Gastroenterology, West China Hospital, Sichuan University) ;
  • Zhao, Ya-Qin (Department of Medical Oncology, West China Hospital, Sichuan University) ;
  • Wang, Xin (Department of Medical Oncology, West China Hospital, Sichuan University) ;
  • Shen, Ya-Li (Department of Medical Oncology, West China Hospital, Sichuan University) ;
  • Liu, Tai-Guo (Department of Medical Oncology, West China Hospital, Sichuan University) ;
  • Cui, Dan-Dan (Department of Medical Oncology, West China Hospital, Sichuan University) ;
  • Xu, Feng (Department of Medical Oncology, West China Hospital, Sichuan University)
  • Published : 2015.06.26

Abstract

Background: To investigate the effects of ASMase mediated endothelial cell apoptosis in multiple hypofractionated irradiations in CT26 tumor bearing mice. Materials and Methods: Thirty-five CT26 tumor bearing mice were subjected to single ionizing radiation (IR) of 0, 3, 6, 9, 12, 15, 18 Gy. Eight hours after IR, the mice were sacrificed and tumor tissues were used for CD31 immunohistochemistry staining, TUNEL and CD31 double staining, ASMase activity assay. Then 6 and 12 Gy were chosen for multiple hypofractionated IR experiments according to the above results. Each time after IR, 5 mice were sacrificed and assayed as above. Results: The ASMase activities were increased significantly after a single IR of 12 Gy or higher which was accompanied with remarkable increased endothelial cell apoptosis and decreased MVD. For 6 Gy which was not high enough to trigger ASMase activation, after 2 or more times of IR, the ASMase activities were significantly increased accompanied with remarkable increased endothelial cell apoptosis and decreased MVD. While for 12 Gy, after 2 or more times of IR, the ASMase activities and endothelial cell apoptosis rates were maintained without remarkable increase; however, the MVD was significantly decreased. What's more, the cancer cell apoptosis rates were significantly increased after multiple IR for both 6 Gy and 12 Gy. Conclusions: ASMase mediated endothelial cell apoptosis may play an important role in the process of multiple hypofractionated IR for CT26 colorectal carcinoma.

Keywords

ASMase;endothelial cell;hypofractionated irradiations;CT26 tumor bearing mice

Acknowledgement

Supported by : National Natural Scientific Foundation of China

References

  1. Bruns CJ, Shrader M, Harbison MT, et al (2002). Effect of the vascular endothelial growth factor receptor-2 antibody DC101 plus gemcitabine on growth, metastasis and angiogenesis of human pancreatic cancer growing orthotopically in nude mice. Int J Cancer, 102, 101-8. https://doi.org/10.1002/ijc.10681
  2. Chapet O, Udrescu C, Devonec M, et al (2013). Prostate hypofractionated radiation therapy: injection of hyaluronic acid to better preserve the rectal wall. Int J Radiat Oncol Biol Phys, 86, 72-6. https://doi.org/10.1016/j.ijrobp.2012.11.027
  3. Corre I, Niaudet C, Paris F (2010). Plasma membrane signaling induced by ionizing radiation. Mutat Res, 704, 61-7. https://doi.org/10.1016/j.mrrev.2010.01.014
  4. Dimanche-Boitrel MT, Meurette O, Rebillard A, Lacour S (2005). Role of early plasma membrane events in chemotherapyinduced cell death. Drug Resist Updat, 8, 5-14. https://doi.org/10.1016/j.drup.2005.02.003
  5. Fuks Z, Kolesnick R (2005). Engaging the vascular component of the tumor response. Cancer Cell, 8, 89-91. https://doi.org/10.1016/j.ccr.2005.07.014
  6. Garcia-Barros M, Paris F, Cordon-Cardo C, et al (2003). Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science, 300, 1155-9. https://doi.org/10.1126/science.1082504
  7. Garcia-Barros M, Thin TH, Maj J, et al (2010). Impact of stromal sensitivity on radiation response of tumors implanted in SCID hosts revisited. Cancer Res, 70, 8179-86. https://doi.org/10.1158/0008-5472.CAN-10-1871
  8. Gulbins E, Kolesnick R (2003). Raft ceramide in molecular medicine. Oncogene, 22, 7070-7. https://doi.org/10.1038/sj.onc.1207146
  9. Haimovitz-Friedman A, Kan CC, Ehleiter D, et al (1994). Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med, 180, 525-35. https://doi.org/10.1084/jem.180.2.525
  10. Hua G, Kolesnick R (2013). Using ASMase knockout mice to model human diseases. Handb Exp Pharmacol, 216, 29-54. https://doi.org/10.1007/978-3-7091-1511-4_2
  11. Kolesnick R, Fuks Z (2003). Radiation and ceramide-induced apoptosis. Oncogene, 22, 5897-906. https://doi.org/10.1038/sj.onc.1206702
  12. Koukourakis MI, Giatromanolaki A, Tsoutsou P, et al (2011). Bevacizumab, capecitabine, amifostine, and preoperative hypofractionated accelerated radiotherapy (HypoArc) for rectal cancer: a Phase II study. Int J Radiat Oncol Biol Phys, 80, 492-8. https://doi.org/10.1016/j.ijrobp.2010.02.037
  13. Lan J, Wan XL, Deng L, et al (2013). Ablative hypofractionated radiotherapy normalizes tumor vasculature in lewis lung carcinoma mice model. Radiat Res, 179, 458-64. https://doi.org/10.1667/RR3116.1
  14. Li YQ, Chen P, Haimovitz-Friedman A, et al (2003). Endothelial apoptosis initiates acute blood-brain barrier disruption after ionizing radiation. Cancer Res, 63, 5950-6.
  15. Li ZJ, Zhu H, Ma BY, et al (2012). Inhibitory effect of Bifidobacterium infantis-mediated sKDR prokaryotic expression system on angiogenesis and growth of Lewis lung cancer in mice. BMC Cancer, 12, 155. https://doi.org/10.1186/1471-2407-12-155
  16. Longo CA, Tyler D, Mallampalli RK (1997). Sphingomyelin metabolism is developmentally regulated in rat lung. Am J Respir Cell Mol Biol, 16, 605-12. https://doi.org/10.1165/ajrcmb.16.5.9160843
  17. Moeller BJ, Dreher MR, Rabbani ZN, et al (2005). Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell, 8, 99-110. https://doi.org/10.1016/j.ccr.2005.06.016
  18. Nava VE, Cuvillier O, Edsall LC, et al (2000). Sphingosine enhances apoptosis of radiation-resistant prostate cancer cells. Cancer Res, 60, 4468-74.
  19. Osti MF, Agolli L, Valeriani M, et al (2013). Image guided hypofractionated 3-dimensional radiation therapy in patients with inoperable advanced stage non-small cell lung cancer. Int J Radiat Oncol Biol Phys, 85, 157-63. https://doi.org/10.1016/j.ijrobp.2012.03.003
  20. Paris F, Fuks Z, Kang A, et al (2001). Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science, 293, 293-7. https://doi.org/10.1126/science.1060191
  21. Park HJ, Griffin RJ, Hui S, et al (2012). Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS). Radiat Res, 177, 311-27. https://doi.org/10.1667/RR2773.1
  22. Pena LA, Fuks Z, Kolesnick RN (2000). Radiation-induced apoptosis of endothelial cells in the murine central nervous system: protection by fibroblast growth factor and sphingomyelinase deficiency. Cancer Res, 60, 321-7.
  23. Pollard JM, Gatti RA (2009). Clinical radiation sensitivity with DNA repair disorders: an overview. Int J Radiat Oncol Biol Phys, 74, 1323-31. https://doi.org/10.1016/j.ijrobp.2009.02.057
  24. Rotolo JA, Maj JG, Feldman R, et al (2008). Bax and Bak do not exhibit functional redundancy in mediating radiationinduced endothelial apoptosis in the intestinal mucosa. Int J Radiat Oncol Biol Phys, 70, 804-15. https://doi.org/10.1016/j.ijrobp.2007.11.043
  25. Rotolo JA, Zhang J, Donepudi M, et al (2005). Caspase-dependent and -independent activation of acid sphingomyelinase signaling. J Biol Chem, 280, 26425-34. https://doi.org/10.1074/jbc.M414569200
  26. Samet D, Barenholz Y (1999). Characterization of acidic and neutral sphingomyelinase activities in crude extracts of HL-60 cells. Chem Phys Lipids, 102, 65-77. https://doi.org/10.1016/S0009-3084(99)00076-6
  27. Santana P, Pena LA, Haimovitz-Friedman A, et al (1996). Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell, 86, 189-99. https://doi.org/10.1016/S0092-8674(00)80091-4
  28. Saponaro C, Malfettone A, Ranieri G, et al (2013). VEGF, HIF-1alpha expression and MVD as an angiogenic network in familial breast cancer. PLoS One, 8, 53070. https://doi.org/10.1371/journal.pone.0053070
  29. Stancevic B, Kolesnick R (2010). Ceramide-rich platforms in transmembrane signaling. FEBS Lett, 584, 1728-40. https://doi.org/10.1016/j.febslet.2010.02.026
  30. Truman JP, Al Gadban MM, Smith KJ, Hammad SM (2011). Acid sphingomyelinase in macrophage biology. Cell Mol Life Sci, 68, 3293-305. https://doi.org/10.1007/s00018-011-0686-6
  31. Truman JP, Garcia-Barros M, Kaag M, et al (2010). Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery. PLoS One, 5, 9d04-4d120568a897.
  32. Utermohlen O, Karow U, Lohler J, Kronke M (2003). Severe impairment in early host defense against Listeria monocytogenes in mice deficient in acid sphingomyelinase. J Immunol, 170, 2621-8. https://doi.org/10.4049/jimmunol.170.5.2621
  33. Xu J, Yan X, Gao R, et al (2010). Effect of irradiation on microvascular endothelial cells of parotid glands in the miniature pig. Int J Radiat Oncol Biol Phys, 78, 897-903. https://doi.org/10.1016/j.ijrobp.2010.05.048
  34. Zeidan YH, Hannun YA (2010). The acid sphingomyelinase/ceramide pathway: biomedical significance and mechanisms of regulation. Curr Mol Med, 10, 454-66. https://doi.org/10.2174/156652410791608225
  35. Zeidan YH, Wu BX, Jenkins RW, et al (2008). A novel role for protein kinase Cdelta-mediated phosphorylation of acid sphingomyelinase in UV light-induced mitochondrial injury. Faseb J, 22, 183-93. https://doi.org/10.1096/fj.07-8967com
  36. Zeng H, Yuan Z, Zhu H, et al (2012). Expression of hPNAS-4 radiosensitizes lewis lung cancer. Int J Radiat Oncol Biol Phys, 24, 24.
  37. Zhang Y, Mattjus P, Schmid PC, et al (2001). Involvement of the acid sphingomyelinase pathway in uva-induced apoptosis. J Biol Chem, 276, 11775-82. https://doi.org/10.1074/jbc.M006000200
  38. Zhu H, Li Z, Mao S, et al (2011). Antitumor effect of sFlt-1 gene therapy system mediated by Bifidobacterium Infantis on Lewis lung cancer in mice. Cancer Gene Ther, 18, 884-96. https://doi.org/10.1038/cgt.2011.57

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