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Molecular Cancer
Published in: Molecular Cancer 1/2010

Open Access 01-12-2010 | Research

TRAIL sensitize MDR cells to MDR-related drugs by down-regulation of P-glycoprotein through inhibition of DNA-PKcs/Akt/GSK-3β pathway and activation of caspases

Authors: Suk-Bin Seo, Jung-Gu Hur, Mi-Ju Kim, Jae-Won Lee, Hak-Bong Kim, Jae-Ho Bae, Dong-Wan Kim, Chi-Dug Kang, Sun-Hee Kim

Published in: Molecular Cancer | Issue 1/2010

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Abstract

Background

The development of new modulator possessing high efficacy, low toxicity and high selectivity is a pivotal approach to overcome P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in cancer treatment. In this study, we suggest a new molecular mechanism that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) down-regulates P-glycoprotein (P-gp) through inhibition of DNA-PKcs/Akt/GSK-3β pathway and activation of caspases and thereby sensitize MDR cells to MDR-related drugs.

Results

MDR variants, CEM/VLB10-2, CEM/VLB55-8 and CEM/VLB100 cells, with gradually increased levels of P-gp derived from human lymphoblastic leukemia CEM cells, were gradually more susceptible to TRAIL-induced apoptosis and cytotoxicity than parental CEM cells. The P-gp level of MDR variants was positively correlated with the levels of DNA-PKcs, pAkt, pGSK-3β and c-Myc as well as DR5 and negatively correlated with the level of c-FLIPs. Hypersensitivity of CEM/VLB100 cells to TRAIL was accompanied by the activation of mitochondrial apoptotic pathway as well as the activation of initiator caspases. In addition, TRAIL-induced down-regulation of DNA-PKcs/Akt/GSK-3β pathway and c-FLIP and up-regulation of cell surface expression of death receptors were associated with the increased susceptibility to TRAIL of MDR cells. Moreover, TRAIL inhibited P-gp efflux function via caspase-3-dependent degradation of P-gp as well as DNA-PKcs and subsequently sensitized MDR cells to MDR-related drugs such as vinblastine and doxorubicin. We also found that suppression of DNA-PKcs by siRNA enhanced the susceptibility of MDR cells to vincristine as well as TRAIL via down-regulation of c-FLIP and P-gp expression and up-regulation of DR5.

Conclusion

This study showed for the first time that the MDR variant of CEM cells was hypersensitive to TRAIL due to up-regulation of DR5 and concomitant down-regulation of c-FLIP, and degradation of P-gp and DNA-PKcs by activation of caspase-3 might be important determinants of TRAIL-induced sensitization of MDR cells to MDR-related drugs. Therefore, combination of TRAIL and chemotherapeutic drugs may be a good strategy for treatment of cancer with multidrug resistance.
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Literature
1.
Gottesman MM, Fojo T, Bates SE: Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002, 2: 48-58. 10.1038/nrc706CrossRefPubMed
2.
Tsuruo T, Naito M, Tomida A, Fujita N, Mashima T, Sakamoto H, Haga N: Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal. Cancer Sci. 2003, 94: 15-21. 10.1111/j.1349-7006.2003.tb01345.xCrossRefPubMed
3.
Tan B, Piwnica-Worms D, Ratner L: Multidrug resistance transporters and modulation. Curr Opin Oncol. 2000, 12: 450-458. 10.1097/00001622-200009000-00011CrossRefPubMed
4.
Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM: Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006, 5: 219-234. 10.1038/nrd1984CrossRefPubMed
5.
Trock BJ, Leonessa F, Clarke R: Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance. J Natl Cancer Inst. 1997, 89: 917-931. 10.1093/jnci/89.13.917CrossRefPubMed
6.
Norgaard JM, Bukh A, Langkjer ST, Clausen N, Palshof T, Hokland P: MDR1 gene expression and drug resistance of AML cells. Br J Haematol. 1998, 100: 534-540. 10.1046/j.1365-2141.1998.00593.xCrossRefPubMed
7.
Steinbach D, Legrand O: ABC transporters and drug resistance in leukemia: was P-gp nothing but the first head of the Hydra?. Leukemia. 2007, 21: 1172-1176. 10.1038/sj.leu.2404692CrossRefPubMed
8.
Ivy SP, Olshefski RS, Taylor BJ, Patel KM, Reaman GH: Correlation of P-glycoprotein expression and function in childhood acute leukemia: a children's cancer group study. Blood. 1996, 88: 309-318.PubMed
9.
Li X, Li JP, Yuan HY, Gao X, Qu XJ, Xu WF, Tang W: Recent advances in P-glycoprotein-mediated multidrug resistance reversal mechanisms. Methods Find Exp Clin Pharmacol. 2007, 29: 607-617. 10.1358/mf.2007.29.9.1139054CrossRefPubMed
10.
Kim SH, Um JH, Dong-Won B, Kwon BH, Kim DW, Chung BS, Kang CD: Potentiation of chemosensitivity in multidrug-resistant human leukemia CEM cells by inhibition of DNA-dependent protein kinase using wortmannin. Leuk Res. 2000, 24: 917-925. 10.1016/S0145-2126(00)00061-8CrossRefPubMed
11.
Bolderson E, Richard DJ, Zhou BB, Khanna KK: Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair. Clin Cancer Res. 2009, 15: 6314-6320. 10.1158/1078-0432.CCR-09-0096CrossRefPubMed
12.
Zhong X, Safa AR: Phosphorylation of RNA helicase A by DNA-dependent protein kinase is indispensable for expression of the MDR1 gene product P-glycoprotein in multidrug-resistant human leukemia cells. Biochemistry. 2007, 46: 5766-5775. 10.1021/bi700063bCrossRefPubMed
13.
West KA, Castillo SS, Dennis PA: Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat. 2002, 5: 234-248. 10.1016/S1368-7646(02)00120-6CrossRefPubMed
14.
Chiarini F, Del Sole M, Mongiorgi S, Gaboardi GC, Cappellini A, Mantovani I, Follo MY, McCubrey JA, Martelli AM: The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism. Leukemia. 2008, 22: 1106-1116. 10.1038/leu.2008.79CrossRefPubMed
15.
Choi BH, Kim CG, Lim Y, Shin SY, Lee YH: Curcumin down-regulates the multidrug-resistance mdr1b gene by inhibiting the PI3K/Akt/NF kappa B pathway. Cancer Lett. 2008, 259: 111-118. 10.1016/j.canlet.2007.10.003CrossRefPubMed
16.
Zhang Y, Qu X, Hu X, Yang X, Hou K, Teng Y, Zhang J, Sada K, Liu Y: Reversal of P-glycoprotein-mediated multi-drug resistance by the E3 ubiquitin ligase Cbl-b in human gastric adenocarcinoma cells. J Pathol. 2009, 218: 248-255. 10.1002/path.2533CrossRefPubMed
17.
Bozulic L, Surucu B, Hynx D, Hemmings BA: PKBalpha/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival. Mol Cell. 2008, 30: 203-213. 10.1016/j.molcel.2008.02.024CrossRefPubMed
18.
Feng J, Park J, Cron P, Hess D, Hemmings BA: Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J Biol Chem. 2004, 279: 41189-41196. 10.1074/jbc.M406731200CrossRefPubMed
19.
Beurel E, Jope RS: The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Prog Neurobiol. 2006, 79: 173-189. 10.1016/j.pneurobio.2006.07.006PubMedCentralCrossRefPubMed
20.
21.
Falschlehner C, Emmerich CH, Gerlach B, Walczak H: TRAIL signalling: decisions between life and death. Int J Biochem Cell Biol. 2007, 39: 1462-1475. 10.1016/j.biocel.2007.02.007CrossRefPubMed
22.
Day TW, Huang S, Safa AR: c-FLIP knockdown induces ligand-independent DR5-, FADD-, caspase-8-, and caspase-9-dependent apoptosis in breast cancer cells. Biochem Pharmacol. 2008, 76: 1694-1704. 10.1016/j.bcp.2008.09.007PubMedCentralCrossRefPubMed
23.
Nam SY, Amoscato AA, Lee YJ: Low glucose-enhanced TRAIL cytotoxicity is mediated through the ceramide-Akt-FLIP pathway. Oncogene. 2002, 21: 337-346. 10.1038/sj.onc.1205068CrossRefPubMed
24.
Cenni V, Maraldi NM, Ruggeri A, Secchiero P, Del Coco R, De Pol A, Cocco L, Marmiroli S: Sensitization of multidrug resistant human ostesarcoma cells to Apo2 Ligand/TRAIL-induced apoptosis by inhibition of the Akt/PKB kinase. Int J Oncol. 2004, 25: 1599-1608.PubMed
25.
Park SJ, Wu CH, Choi MR, Najafi F, Emami A, Safa AR: P-glycoprotein enhances TRAIL-triggered apoptosis in multidrug resistant cancer cells by interacting with the death receptor DR5. Biochem Pharmacol. 2006, 72: 293-307. 10.1016/j.bcp.2006.04.024CrossRefPubMed
26.
Krishna R, Mayer LD: Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci. 2000, 11: 265-283. 10.1016/S0928-0987(00)00114-7CrossRefPubMed
27.
Safa AR, Day TW, Wu CH: Cellular FLICE-like inhibitory protein (C-FLIP): a novel target for cancer therapy. Curr Cancer Drug Targets. 2008, 8: 37-46. 10.2174/156800908783497087PubMedCentralCrossRefPubMed
28.
An J, Yang DY, Xu QZ, Zhang SM, Huo YY, Shang ZF, Wang Y, Wu DC, Zhou PK: DNA-dependent protein kinase catalytic subunit modulates the stability of c-Myc oncoprotein. Mol Cancer. 2008, 7: 32- 10.1186/1476-4598-7-32PubMedCentralCrossRefPubMed
29.
Nakamura Y, Sato H, Motokura T: Development of multidrug resistance due to multiple factors including P-glycoprotein overexpression under K-selection after MYC and HRAS oncogene activation. Int J Cancer. 2006, 118: 2448-2454. 10.1002/ijc.21691CrossRefPubMed
30.
He Y, Zhang J, Yuan Y: The role of c-myc in regulating mdr1 gene expression in tumor cell line KB. Chin Med J (Engl). 2000, 113: 848-851.
31.
Klefstrom J, Verschuren EW, Evan G: c-Myc augments the apoptotic activity of cytosolic death receptor signaling proteins by engaging the mitochondrial apoptotic pathway. J Biol Chem. 2002, 277: 43224-43232. 10.1074/jbc.M206967200CrossRefPubMed
32.
Zhang J, Hawkins SF, Glenn MA, Lin K, Johnson GG, Carter A, Cawley JC, Pettitt AR: Akt is activated in chronic lymhocytic leukemia cells and delivers a pro-survival signal: the therapeutic potential of Akt inhibition. Haematologica. 2010, 95: 110-118. 10.3324/haematol.2009.010272CrossRef
33.
Mantovani I, Cappellini A, Tazzari PL, Papa V, Cocco L, Martelli AM: Caspase-dependent cleavage of 170-kDa P-glycoprotein during apoptosis of human T-lymphoblastoid CEM cells. J Cell Physiol. 2006, 207: 836-844. 10.1002/jcp.20628CrossRefPubMed
34.
Affar EB, Germain M, Winstall E, Vodenicharov M, Shah RG, Salvesen GS, Poirier GG: Caspase-3-mediated processing of poly(ADP-ribose) glycohydrolase during apoptosis. J Biol Chem. 2001, 276: 2935-2942. 10.1074/jbc.M007269200CrossRefPubMed
35.
Graham KL, Gustin KE, Rivera C, Kuyumcu-Martinez NM, Choe SS, Lloyd RE, Sarnow P, Utz PJ: Proteolytic cleavage of the catalytic subunit of DNA-dependent protein kinase during poliovirus infection. J Virol. 2004, 78: 6313-6321. 10.1128/JVI.78.12.6313-6321.2004PubMedCentralCrossRefPubMed
36.
Park SJ, Kim MJ, Kim HB, Sohn HY, Bae JH, Kang CD, Kim SH: Cotreatment with apicidin overcomes TRAIL resistance via inhibition of Bcr-Abl signaling pathway in K562 leukemia cells. Exp Cell Res. 2009, 315: 1809-1818. 10.1016/j.yexcr.2009.02.024CrossRefPubMed
37.
Lee NS, Cheong HJ, Kim SJ, Kim SE, Kim CK, Lee KT, Park SK, Baick SH, Hong DS, Park HS, Won JH: Ex vivo purging of leukemia cells using tumor-necrosis-factor-related apoptosis-inducing ligand in hematopoietic stem cell transplantation. Leukemia. 2003, 17: 1375-1383. 10.1038/sj.leu.2402960CrossRefPubMed
38.
Nakamura H, Kawakami A, Iwamoto N, Ida H, Koji T, Eguchi K: Rapid and significant induction of TRAIL-mediated type II cells in apoptosis of primary salivary epithelial cells in primary Sjogren's syndrome. Apoptosis. 2008, 13: 1322-1330. 10.1007/s10495-008-0261-2CrossRefPubMed
39.
Wang Y, Engels IH, Knee DA, Nasoff M, Deveraux QL, Quon KC: Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway. Cancer Cell. 2004, 5: 501-512. 10.1016/S1535-6108(04)00113-8CrossRefPubMed
40.
Ricci MS, Jin Z, Dews M, Yu D, Thomas-Tikhonenko A, Dicker DT, El-Deiry WS: Direct repression of FLIP expression by c-myc is a major determinant of TRAIL sensitivity. Mol Cell Biol. 2004, 24: 8541-8555. 10.1128/MCB.24.19.8541-8555.2004PubMedCentralCrossRefPubMed
41.
Han Z, Hong L, Han Y, Wu K, Han S, Shen H, Li C, Yao L, Qiao T, Fan D: Phospho Akt mediates multidrug resistance of gastric cancer cells through regulation of P-gp, Bcl-2 and Bax. J Exp Clin Cancer Res. 2007, 26: 261-268.PubMed
42.
Lim JC, Kania KD, Wijesuriya H, Chawla S, Sethi JK, Pulaski L, Romero IA, Couraud PO, Weksler BB, Hladky SB, Barrand MA: Activation of beta-catenin signalling by GSK-3 inhibition increases p-glycoprotein expression in brain endothelial cells. J Neurochem. 2008, 106: 1855-1865.PubMedCentralPubMed
43.
David E, Sinha R, Chen J, Sun SY, Kaufman JL, Lonial S: Perifosine synergistically enhances TRAIL-induced myeloma cell apoptosis via up-regulation of death receptors. Clin Cancer Res. 2008, 14: 5090-5098. 10.1158/1078-0432.CCR-08-0016CrossRefPubMed
44.
Nam SY, Jung GA, Hur GC, Chung HY, Kim WH, Seol DW, Lee BL: Upregulation of FLIP(S) by Akt, a possible inhibition mechanism of TRAIL-induced apoptosis in human gastric cancers. Cancer Sci. 2003, 94: 1066-1073. 10.1111/j.1349-7006.2003.tb01402.xCrossRefPubMed
45.
Gul O, Basaga H, Kutuk O: Apoptotic blocks and chemotherapy resistance: strategies to identify Bcl-2 protein signatures. Brief Funct Genomic Proteomic. 2008, 7: 27-34. 10.1093/bfgp/eln002CrossRefPubMed
46.
Del Poeta G, Bruno A, Del Principe MI, Venditti A, Maurillo L, Buccisano F, Stasi R, Neri B, Luciano F, Siniscalchi A: Deregulation of the mitochondrial apoptotic machinery and development of molecular targeted drugs in acute myeloid leukemia. Curr Cancer Drug Targets. 2008, 8: 207-222. 10.2174/156800908784293640CrossRefPubMed
47.
Nuessler V, Stotzer O, Gullis E, Pelka-Fleischer R, Pogrebniak A, Gieseler F, Wilmanns W: Bcl-2, bax and bcl-xL expression in human sensitive and resistant leukemia cell lines. Leukemia. 1999, 13: 1864-1872. 10.1038/sj/leu/2401571CrossRefPubMed
48.
Ji M, Li J, Yu H, Ma D, Ye J, Sun X, Ji C: Simultaneous targeting of MCL1 and ABCB1 as a novel strategy to overcome drug resistance in human leukaemia. Br J Haematol. 2009, 145: 648-656. 10.1111/j.1365-2141.2009.07678.xCrossRefPubMed
Metadata
Title
TRAIL sensitize MDR cells to MDR-related drugs by down-regulation of P-glycoprotein through inhibition of DNA-PKcs/Akt/GSK-3β pathway and activation of caspases
Authors
Suk-Bin Seo
Jung-Gu Hur
Mi-Ju Kim
Jae-Won Lee
Hak-Bong Kim
Jae-Ho Bae
Dong-Wan Kim
Chi-Dug Kang
Sun-Hee Kim
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2010
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-9-199

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