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
<p>Abstract</p> <p>Background</p> <p>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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2010-07-01
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| Series: | Molecular Cancer |
| Online Access: | http://www.molecular-cancer.com/content/9/1/199 |
| _version_ | 1818916028293316608 |
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| author | Kim Dong-Wan Bae Jae-Ho Kim Hak-Bong Lee Jae-Won Kim Mi-Ju Hur Jung-Gu Seo Suk-Bin Kang Chi-Dug Kim Sun-Hee |
| author_facet | Kim Dong-Wan Bae Jae-Ho Kim Hak-Bong Lee Jae-Won Kim Mi-Ju Hur Jung-Gu Seo Suk-Bin Kang Chi-Dug Kim Sun-Hee |
| author_sort | Kim Dong-Wan |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>MDR variants, CEM/VLB<sub>10-2</sub>, CEM/VLB<sub>55-8 </sub>and CEM/VLB<sub>100 </sub>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/VLB<sub>100 </sub>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.</p> <p>Conclusion</p> <p>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.</p> |
| first_indexed | 2024-12-20T00:11:39Z |
| format | Article |
| id | doaj.art-37cd4968aced43afa10db4a8256f77c5 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-20T00:11:39Z |
| publishDate | 2010-07-01 |
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| series | Molecular Cancer |
| spelling | doaj.art-37cd4968aced43afa10db4a8256f77c52022-12-21T20:00:29ZengBMCMolecular Cancer1476-45982010-07-019119910.1186/1476-4598-9-199TRAIL 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 caspasesKim Dong-WanBae Jae-HoKim Hak-BongLee Jae-WonKim Mi-JuHur Jung-GuSeo Suk-BinKang Chi-DugKim Sun-Hee<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>MDR variants, CEM/VLB<sub>10-2</sub>, CEM/VLB<sub>55-8 </sub>and CEM/VLB<sub>100 </sub>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/VLB<sub>100 </sub>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.</p> <p>Conclusion</p> <p>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.</p>http://www.molecular-cancer.com/content/9/1/199 |
| spellingShingle | Kim Dong-Wan Bae Jae-Ho Kim Hak-Bong Lee Jae-Won Kim Mi-Ju Hur Jung-Gu Seo Suk-Bin Kang Chi-Dug Kim Sun-Hee 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 Molecular Cancer |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | http://www.molecular-cancer.com/content/9/1/199 |
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