The proteasome inhibition enhances apoptosis by P53 expression and the dissipation of mitochondrial transmembrane potential in TRAIL-resistant lung cancer cells

Proteasome 억제에 의한 P53의 발현과 미토콘드리아 막 전압의 소실로 TRAIL에 저항하는 폐암세포의 사멸 강화

  • Seol, Jae-Won (Center for Healthcare Technology Development, and Bio-safety Research Institute, College of Veterinary Medicine, Chonbuk National University) ;
  • Park, Sang-Youel (Center for Healthcare Technology Development, and Bio-safety Research Institute, College of Veterinary Medicine, Chonbuk National University)
  • 설재원 (전북대학교 헬스케어 기술개발사업단, 수의과대학 생체안전성연구소) ;
  • 박상열 (전북대학교 헬스케어 기술개발사업단, 수의과대학 생체안전성연구소)
  • Accepted : 2009.02.10
  • Published : 2009.03.30

Abstract

The ubiquitin-proteasome mediated protein degradation pathway plays an important role in regulating both cell proliferation and cell death. Proteasome inhibitors are well known to induce apoptosis in various human cancer cell lines. We investigated the effect of combined treatment with proteasome inhibitor and TRAIL, and a possible mechanism of the enhancing apoptosis by the both treatment, on TRAIL-resistant non-small cell lung cancer. A549 cells were exposed to the N-Acetyl-Leu-Leu-Norleu-al (ALLN) as a proteasome inhibitor and then treated with recombinant TRAIL protein. In A549 cells under proteasome inhibition conditions by pretreatment with ALLN, TRAIL treatment significantly decreased cell viability compared to that ALLN and TRAIL alone treatment. Also, the both treatment induced cell damage through DNA fragmentation and p53 expression. In addition, the combined treatment of both markedly increased caspase-8 activation, especially the exposure for 2 h, and Bax expression and induced the dissipation of mitochondrial transmembrane potential in A549 cells. Taken together, these findings showed that proteasome inhibition by ALLN enhanced TRAIL-induced apoptosis via DNA degradation by activated P53 and mitochondrial transmembrane potential loss by caspase-8 activation and bax expression. Therefore, our results suggest that proteasome inhibitor may be used a very effectively chemotherapeutic agent for the tumor treatment, especially TRAIL-resistant tumor cell.

Keywords

References

  1. An WG, Hwang SG, Trepel JB, Blagosklonny MV.Protease inhibitor-induced apoptosis: accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis areindependent markers of proteasome inhibition. Leukemia 2000, 14, 1276-1283 https://doi.org/10.1038/sj.leu.2401812
  2. Boldin MP, Goncharov TM, Goltsev YV, Wallach D. Involvement of MACH, a novel MORT1/FADDinteractingprotease, in Fas/APO-1- and TNF receptorinducedcell death. Cell 1996, 85, 803-815 https://doi.org/10.1016/S0092-8674(00)81265-9
  3. Brooks AD, Ramirez T, Toh U, Onksen J, Elliott PJ,Murphy WJ, Sayers TJ. The Proteasome InhibitorBortezomib (Velcade) Sensitizes Some Human TumorCells to Apo2L/TRAIL-Mediated Apoptosis. Ann N YAcad Sci 2005, 1059, 160-167 https://doi.org/10.1196/annals.1339.042
  4. Cha SS, Kim MS, Choi YH, Sung BJ, Shin NK,Shin HC, Sung YC, Oh BH. 2.8 A resolution crystalstructure of human TRAIL, a cytokine with selectiveantitumor activity. Immunity 1999, 11, 253-261 https://doi.org/10.1016/S1074-7613(00)80100-4
  5. Chen JJ, Chou CW, Chang YF, Chen CC.Proteasome inhibitors enhance TRAIL-induced apoptosisthrough the intronic regulation of DR5: involvement of NF-kappa B and reactive oxygen species-mediated p53activation. J Immunol 2008, 180, 8030-8039 https://doi.org/10.4049/jimmunol.180.12.8030
  6. Coux O, Tanaka K, Goldberg AL. Structure andfunctions of the 20S and 26S proteasomes. Annu RevBiochem 1996, 65, 801-847 https://doi.org/10.1146/annurev.bi.65.070196.004101
  7. Drexler HC. Activation of the cell death program byinhibition of proteasome function. Proc Natl Acad SciUSA 1997, 94, 855-860 https://doi.org/10.1073/pnas.94.3.855
  8. Ganten TM, Koschny R, Haas TL, Sykora J, Li-Weber M, Herzer K, Walczak H. Proteasomeinhibition sensitizes hepatocellular carcinoma cells, butnot human hepatocytes, to TRAIL. Hepatology 2005,42, 588-597 https://doi.org/10.1002/hep.20807
  9. Goldberg AL, Stein R, Adams J. New insights intoproteasome function: from archaebacteria to drugdevelopment. Chem Biol 1995, 2, 503-508 https://doi.org/10.1016/1074-5521(95)90182-5
  10. Griffith TS, Anderson RD, Davidson BL, WilliamsRD, Ratliff TL. Adenoviral-mediated transfer of theTNF-related apoptosis-inducing ligand/Apo-2 ligandgene induces tumor cell apoptosis. J Immunol 2000,165, 2886-2894 https://doi.org/10.4049/jimmunol.165.5.2886
  11. Hammond EM, Giaccia AJ. The role of p53 inhypoxia-induced apoptosis. Biochem Biophys ResCommun 2005, 331, 718-725 https://doi.org/10.1016/j.bbrc.2005.03.154
  12. Hansson LO, Friedler A, Freund S, Rudiger S,Fersht AR. Two sequence motifs from HIF-1alphabind to the DNA-binding site of p53. Proc Natl AcadSci USA 2002, 99, 10305-10309 https://doi.org/10.1073/pnas.122347199
  13. He Q, Huang Y, Sheikh MS. Proteasome inhibitorMG132 upregulates death receptor 5 and cooperateswith Apo2L/TRAIL to induce apoptosis in Baxproficientand -deficient cells. Oncogene 2004, 23,2554-2558 https://doi.org/10.1038/sj.onc.1207351
  14. Hougardy BM, Maduro JH, van der Zee AG, deGroot DJ, van den Heuvel FA, de Vries EG, de JongS. Proteasome inhibitor MG132 sensitizes HPV-positivehuman cervical cancer cells to rhTRAIL-inducedapoptosis. Int J Cancer 2006, 118, 1892-1900 https://doi.org/10.1002/ijc.21580
  15. Hymowitz SG, Christinger HW, Fuh G, Ultsch M,O'Connell M, Kelley RF, Ashkenazi A, de Vos AM.Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5. Mol Cell1999, 4, 563-571 https://doi.org/10.1016/S1097-2765(00)80207-5
  16. Inoue T, Shiraki K, Fuke H, Yamanaka Y, MiyashitaK, Yamaguchi Y, Yamamoto N, Ito K, Sugimoto K,Nakano T. Proteasome inhibition sensitizes hepatocellularcarcinoma cells to TRAIL by suppressingcaspase inhibitors and AKT pathway. Anticancer Drugs2006, 17, 261-268 https://doi.org/10.1097/00001813-200603000-00004
  17. Ishizawa J, Yoshida S, Oya M, Mizuno R, ShinojimaT, Marumo K, Murai M. Inhibition of the ubiquitinproteasomepathway activates stress kinases andinduces apoptosis in renal cancer cells. Int J Oncol2004, 25, 697-702
  18. Kim K, Takimoto R, Dicker DT, Chen Y, Gazitt Y,El-Deiry WS. Enhanced TRAIL sensitivity by p53overexpression in human cancer but not normal celllines. Int J Oncol 2001, 18, 241-247
  19. Kim OH, Lim JH, Woo KJ, Kim YH, Jin IN, HanST, Park JW, Kwon TK. Influence of p53 andp21Waf1 expression on G2/M phase arrest of colorectalcarcinoma HCT116 cells to proteasome inhibitors. Int J Oncol 2004, 24, 935-941
  20. King RW, Deshaies RJ, Peters JM, Kirschner MW.How proteolysis drives the cell cycle. Science 1996,274, 1652-1659 https://doi.org/10.1126/science.274.5293.1652
  21. Kroemer G, Reed JC. Mitochondrial control of celldeath. Nat Med 2000, 6, 513-519 https://doi.org/10.1038/74994
  22. Lashinger LM, Zhu K, Williams SA, Shrader M,Dinney CP, McConkey DJ. Bortezomib abolishestumor necrosis factor-related apoptosis-inducing ligandresistance via a p21-dependent mechanism in humanbladder and prostate cancer cells. Cancer Res 2005, 65,4902-4908 https://doi.org/10.1158/0008-5472.CAN-04-3701
  23. Lim ML, Lum MG, Hansen TM, Roucou X, Nagley P. On the release of cytochrome c from mitochondriaduring cell death signaling. J Biomed Sci 2002, 9, 488-506
  24. Ling YH, Liebes L, Ng B, Buckley M, Elliott PJ,Adams J, Jiang JD, Muggia FM, Perez-Soler R. PS-341, a novel proteasome inhibitor, induces Bcl-2phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. Mol Cancer Ther 2002,1, 841-849
  25. Lu M, Dou QP, Kitson RP, Smith DM, GoldfarbRH. Differential effects of proteasome inhibitors on cellcycle and apoptotic pathways in human YT and Jurkatcells. J Cell Biochem 2006, 97, 122-134 https://doi.org/10.1002/jcb.20543
  26. Mlynarczuk I, Hoser G, Grzela T, Stoklosa T,Wojcik C, Malejczyk J, Jakobisiak M. Augmentedpro-apoptotic effects of TRAIL and proteasomeinhibitor in human promonocytic leukemic U937 cells.Anticancer Res 2001, 21, 1237-1240
  27. Nawrocki ST, Carew JS, Pino MS, Highshaw RA,Dunner K Jr, Huang P, Abbruzzese JL, McConkeyDJ. Bortezomib sensitizes pancreatic cancer cells toendoplasmic reticulum stress-mediated apoptosis. CancerRes 2005, 65, 11658-11666 https://doi.org/10.1158/0008-5472.CAN-05-2370
  28. Newmeyer DD, Ferguson-Miller S. Mitochondria:releasing power for life and unleashing the machineriesof death. Cell 2003, 112, 481-490 https://doi.org/10.1016/S0092-8674(03)00116-8
  29. Pagano M. Cell cycle regulation by the ubiquitinpathway. FASEB J 1997, 11, 1067-1075 https://doi.org/10.1096/fasebj.11.13.9367342
  30. Pitti RM, Marsters SA, Ruppert S, Donahue CJ,Moore A, Ashkenazi A. Induction of apoptosis byApo-2 ligand, a new member of the tumor necrosisfactor cytokine family. J Biol Chem 1996, 271, 12687-12690 https://doi.org/10.1074/jbc.271.22.12687
  31. Santer FR, Bacher N, Moser B, Morandell D,Ressler S, Firth SM, Spoden GA, Sergi C, Baxter RC, Jansen-Durr P, Zwerschke W. Nuclear insulinlikegrowth factor binding protein-3 induces apoptosisand is targeted to ubiquitin/proteasome-dependentproteolysis. Cancer Res 2006, 66, 3024-3033 https://doi.org/10.1158/0008-5472.CAN-05-2013
  32. Seol DW, Billiar TR. Cysteine 230 modulates tumornecrosis factor-related apoptosis-inducing ligand activity.Cancer Res 2000, 60, 3152-3154
  33. Voortman J, Resende TP, Abou El Hassan MA,Giaccone G, Kruyt FA. TRAIL therapy in non-smallcell lung cancer cells: sensitization to death receptormediatedapoptosis by proteasome inhibitor bortezomib.Mol Cancer Ther 2007, 6, 2103-2112 https://doi.org/10.1158/1535-7163.MCT-07-0167
  34. Walczak H, Miller RE, Ariail K, Gliniak B, GriffithTS, Kubin M, Chin W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT,Schuh JC, Lynch DH. Tumoricidal activity of tumornecrosis factor-related apoptosis-inducing ligand invivo. Nat Med 1999, 5, 157-163 https://doi.org/10.1038/5517
  35. Wente MN, Eibl G, Reber HA, Friess H, Buchler MW, Hines OJ. The proteasome inhibitor MG132induces apoptosis in human pancreatic cancer cells.Oncol Rep 2005, 14, 1635-1638
  36. Wiley SR, Schooley K, Smolak PJ, Din WS, HuangCP, Nicholl JK, Sutherland GR, Smith TD, RauchC, Smith CA, Goodwin RG Identification andcharacterization of a new member of the TNF familythat induces apoptosis. Immunity 1995, 3, 673-682 https://doi.org/10.1016/1074-7613(95)90057-8
  37. Yan XB, Yang DS, Gao X, Feng J, Shi ZL, Ye Z.Caspase-8 dependent osteosarcoma cell apoptosisinduced by proteasome inhibitor MG132. Cell Biol Int 2007, 31, 1136-1143 https://doi.org/10.1016/j.cellbi.2007.03.037