Journal of the Korean Society of Food Science and Nutrition (한국식품영양과학회지)

The Korean Society of Food Science and Nutrition (한국식품영양과학회)
권호 표지
DOI QR코드

DOI QR Code

Glutamine Deprivation Inhibits Invasion of Human Prostate Carcinoma LnCap Cells through Inactivation of Matrix Metalloproteinases and Modulation of Tight Junctions

글루타민 결핍에 따른 Tight Junction 및 MMPs 활성 조절을 통한 전립선 암세포의 침윤 억제 현상

  • Shin, Dong Yeok (Dongnam Institute of Radiological & Medicine Sciences) ;
  • Choi, Yung Hyun (Dept. of Biochemistry, College of Oriental Medicine, Dongeui University, Anti-Aging Research Center and Blue-Bio Industry RIC, Dongeui University)
  • 신동역 (동남권원자력의학원) ;
  • 최영현 (동의대학교 한의과대학 생화학교실, 항노화연구소 및 블루바이오소재개발센터)
  • Received : 2013.04.17
  • Accepted : 2013.05.08
  • Published : 2013.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

Cancer cells exhibit increased demand for glutamine-derived carbons to support anabolic processes. Indeed, the spectrum of glutamine-dependent tumors and the mechanisms through which glutamine supports cancer metabolism remain areas of active investigation. In the present study, we investigated the effects of glutamine deprivation on the correlation between tightening of tight junctions (TJs) and anti-invasive activity in human prostate carcinoma LnCap cells. Glutamine deprivation markedly inhibited cell motility and invasiveness in a time-dependent manner. The anti-invasive activity of glutamine deprivation was associated with an increased tightness of the TJ, which was demonstrated by an increase in transepithelial electrical resistance (TER). The activities of matrix metalloproteinase (MMP)-2 and MMP-9 were inhibited in a time-dependent fashion by glutamine deprivation, which was correlated with a decrease in expression of their mRNA and proteins and up-regulation of tissue inhibitors of metalloproteinases (TIMPs) expression. Furthermore, glutamine deprivation repressed the levels of the claudin family members, which are major components of TJs that play a key role in the control and selectivity of paracellular transport. Moreover, the levels of E-cadherin, a type I transmembrane glycoprotein, and snail, an epithelial to mesenchymal transition regulator and zinc finger transcription factor, were markedly modulated by glutamine deprivation. Taken together, these findings suggest that TJs and MMPs are critical targets of glutamine deprivation-induced anti-invasion in human prostate carcinoma LnCap cells.

암세포를 포함한 생체 내 빠른 분열을 요구하는 세포 집단에서 세포 내 구성요소 및 에너지원으로서 글루타민의 요구량이 증대되지만, 종양세포의 글루타민 의존적 대사작용에 관한 기전은 여전히 잘 알려진 바 없다. 본 연구에서는 LnCaP 전립선 암세포의 이동성 및 침윤성에 미치는 글루타민 결핍효능을 조사하였다. 본 연구의 결과에 의하면 LnCaP 세포에서 글루타민 결핍에 의하여 세포의 이동성 및 세포의 침윤성이 현저하게 억제되었으며, 이러한 이동성 및 침윤성 억제는 TIMPs의 발현 증대에 의한 MMPs의 발현 감소 및 그들의 효소적 활성 저하와 연관성이 있었다. 또한 글루타민이 결핍된 조건에서 배양된 LnCaP 세포에서 TER의 현저한 증가가 관찰되었는데, 이는 TJs의 조절인자인 claudin family 발현의 차단에 의한 것으로 생각되어진다. 본 연구의 결과에 의하면 암세포의 증식에서 글루타민의 결핍은 TJ의 결합력 증대와 MMPs의 활성을 저하시킴으로써 암세포 전이에 가장 기본적인 과정인 암세포의 이동성과 침윤성을 억제시킬 수 있을 것으로 생각된다.

Keywords

References

  1. Woodhouse EC, Chuaqui RF, Liotta LA. 1997. General mechanisms of metastasis. Cancer 80: S1529-S1537. https://doi.org/10.1002/(SICI)1097-0142(19971015)80:8+<1529::AID-CNCR2>3.0.CO;2-F
  2. Chambers AF, Matrisian LM. 1997. Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89: 1260-1270. https://doi.org/10.1093/jnci/89.17.1260
  3. Roeb E, Matern S. 2001. Matrix metalloproteinases: Promoters of tumor invasion and metastasis－A review with focus on gastrointestinal tumors. Z Gastroenterol 39: 807-813. https://doi.org/10.1055/s-2001-17197
  4. Leber MF, Efferth T. 2009. Molecular principles of cancer invasion and metastasis (review). Int J Oncol 34: 881-895.
  5. Morin PJ. 2005. Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res 65:9603-9606. https://doi.org/10.1158/0008-5472.CAN-05-2782
  6. Tagliarino C, Pink JJ, Dubyak GR, Nieminen AL, Boothman DA. 2001. Calcium is a key signaling molecule in $\beta$-lapachone-mediated cell death. J Biol Chem 276: 19150-19159. https://doi.org/10.1074/jbc.M100730200
  7. Kominsky SL, Argani P, Korz D, Evron E, Raman V, Garrett E, Rein A, Sauter G, Kallioniemi OP, Sukumar S. 2003. Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast. Oncogene 22: 2021-2033. https://doi.org/10.1038/sj.onc.1206199
  8. Mauro L, Bartucci M, Morelli C, Andò S, Surmacz E. 2001. IGF-I receptor-induced cell-cell adhesion of MCF-7 breast cancer cells requires the expression of junction protein ZO-1. J Biol Chem 276: 39892-39897. https://doi.org/10.1074/jbc.M106673200
  9. Lombard C, Saulnier J, Wallach J. 2005. Assays of matrix metalloproteinases (MMPs) activities: a review. Biochimie 87: 265-272. https://doi.org/10.1016/j.biochi.2005.01.007
  10. Kohrmann A, Kammerer U, Kapp M, Dietl J, Anacker J. 2009. Expression of matrix metalloproteinases (MMPs) in primary human breast cancer and breast cancer cell lines: New findings and review of the literature. BMC Cancer 9:188. https://doi.org/10.1186/1471-2407-9-188
  11. Gibbs DF, Warner RL, Weiss SJ, Johnson KJ, Varani J. 1999. Characterization of matrix metalloproteinases produced by rat alveolar macrophages. Am J Respir Cell Mol Biol 20: 1136-1144. https://doi.org/10.1165/ajrcmb.20.6.3483
  12. Mook OR, Frederiks WM, Van Noorden CJ. 2004. The role of gelatinases in colorectal cancer progression and metastasis. Biochim Biophys Acta 1705: 69-89.
  13. Lambert E, Dasse E, Haye B, Petitfrere E. 2004. TIMPs as multifacial proteins. Crit Rev Oncol Hematol 49: 187-198. https://doi.org/10.1016/j.critrevonc.2003.09.008
  14. Lee WJ, Hawkins RA, Wina JR, Peterson DR. 1998. Glutamine transport by the blood-brain barrier: a possible mechanism for nitrogen removal. Am J Physiol Cell Physiol 274:C1101-C1107.
  15. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. 2008. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7: 11-20. https://doi.org/10.1016/j.cmet.2007.10.002
  16. Weinberg F, Chandel NS. 2009. Mitochondrial metabolism and cancer. Ann NY Acad Sci 1177: 66-73. https://doi.org/10.1111/j.1749-6632.2009.05039.x
  17. Ko YG, Kim EK, Kim T, Park H, Park HS, Choi EJ, Kim S. 2001. Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signalregulating kinase 1. J Biol Chem 276: 6030-6036. https://doi.org/10.1074/jbc.M006189200
  18. Rosenthal DI, Trotti A. 2009. Strategies for managing radiation-induced mucositis in head and neck cancer. Semin Radiat Oncol 19: 29-34. https://doi.org/10.1016/j.semradonc.2008.09.006
  19. Martin TA, Das T, Mansel RE, Jiang WG. 2006. Synergistic regulation of endothelial tight junctions by antioxidant (Se) and polyunsaturated lipid (GLA) via Claudin-5 modulation. J Cell Biochem 98: 1308-1319. https://doi.org/10.1002/jcb.20860
  20. Wen G, Partridge MA, Li B, Hong M, Liao W, Cheng SK, Zhao Y, Calaf GM, Liu T, Zhou J, Zhang Z, Hei TK. 2011. TGFBI expression reduces in vitro and in vivo metastatic potential of lung and breast tumor cells. Cancer Lett 308:23-32. https://doi.org/10.1016/j.canlet.2011.04.010
  21. Koochekpour S, Majumdar S, Azabdaftari G, Attwood K, Scioneaux R, Subramani D, Manhardt C, Lorusso GD, Willard SS, Thompson H, Shourideh M, Rezaei K, Sartor O, Mohler JL, Vessella RL. 2012. Serum glutamate levels correlate with Gleason score and glutamate blockade decreases proliferation, migration, and invasion and induces apoptosis in prostate cancer cells. Clin Cancer Res 18:5888-5901. https://doi.org/10.1158/1078-0432.CCR-12-1308
  22. Fu YM, Yu ZX, Lin H, Fu X, Meadows GG. 2008. Selective amino acid restriction differentially affects the motility and directionality of DU145 and PC3 prostate cancer cells. Cell Physiol 217: 184-193. https://doi.org/10.1002/jcp.21490
  23. Fu YM, Yu ZX, Li YQ, Ge X, Sanchez PJ, Fu X, Meadows GG. 2003. Specific amino acid dependency regulates invasiveness and viability of androgen-independent prostate cancer cells. Nutr Cancer 45: 60-73. https://doi.org/10.1207/S15327914NC4501_8
  24. Visse R, Nagase H. 2003. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92: 827-839. https://doi.org/10.1161/01.RES.0000070112.80711.3D
  25. Jiang Y, Goldberg ID, Shi YE. 2002. Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene 21:2245-2252. https://doi.org/10.1038/sj.onc.1205291
  26. Mignatti P, Rifkin DB. 1993. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 73: 161-195.
  27. Van Itallie CM, Anderson JM. 2004. The molecular physiology of tight junction pores. Physiology (Bethesda) 19: 331-338. https://doi.org/10.1152/physiol.00027.2004
  28. Boutet A, Esteban MA, Maxwell PH, Nieto MA. 2007. Reactivation of snail genes in renal fibrosis and carcinomas:a process of reversed embryogenesis? Cell Cycle 6: 638-642. https://doi.org/10.4161/cc.6.6.4022
  29. Mendelsohn AH, Lai CK, Shintaku IP, Fishbein MC, Brugman K, Elashoff DA, Abemayor E, Dubinett SM, St John MA. 2012. Snail as a novel marker for regional metastasis in head and neck squamous cell carcinoma. Am J Otolaryngol 33: 6-13. https://doi.org/10.1016/j.amjoto.2010.11.018
  30. Kajita M, McClinic KN, Wade PA. 2004. Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol Cell Biol 24: 7559-7566. https://doi.org/10.1128/MCB.24.17.7559-7566.2004
  31. Li H, Wang H, Wang F, Gu Q, Xu X. 2011. Snail involves in the transforming growth factor $\beta$1-mediated epithelialmesenchymal transition of retinal pigment epithelial cells. PLoS One 6: e23322. https://doi.org/10.1371/journal.pone.0023322
  32. Hirohashi S, Kanai Y. 2003. Cell adhesion system and human cancer morphogenesis. Cancer Sci 94: 575-581. https://doi.org/10.1111/j.1349-7006.2003.tb01485.x
  33. Hsu HP, Shan YS, Jin YT, Lai MD, Lin PW. 2010. Loss of E-cadherin and beta-catenin is correlated with poor prognosis of ampullary neoplasms. J Surg Oncol 101: 356-362.

Cited by

  1. 만성 역류성 식도염에서 황련과 오수유 혼합물이 식도 점막에 미치는 효과 vol.51, pp.4, 2020, https://doi.org/10.22889/kjp.2020.51.4.349