Peroxisome proliferator-activated receptor γ agonists promote TRAIL-induced apoptosis by reducing survivin levels via cyclin D3 repression and cell cycle arrest

Meiling Lu, Toni Kwan, Chunjiang Yu, Feng Chen, Bethany Freedman, Jennifer M. Schafer, Eun Jig Lee, J. Larry Jameson, V. Craig Jordan, Vincent L. Cryns

Research output: Contribution to journalArticle

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Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapy that preferentially induces apoptosis in cancer cells. However, many neoplasms are resistant to TRAIL by mechanisms that are poorly understood. Here we demonstrate that human breast cancer cells, but not normal mammary epithelial cells, are dramatically sensitized to TRAIL-induced apoptosis and caspase activation by peroxisome proliferator-activated receptor γ (PPARγ) agonists of the thiazolidinedione (TZD) class. Although TZDs do not significantly alter the expression of components of the TRAIL signaling pathway, they profoundly reduce protein levels of cyclin D3, but not other D-type cyclins, by decreasing cyclin D3 mRNA levels and by inducing its proteasomal degradation. Importantly, both TRAIL sensitization and reduction in cyclin D3 protein levels induced by TZDs are likely PPARγ-independent because a dominant negative mutant of PPARγ did not antagonize these effects of TZDs, nor were they affected by the expression levels of PPARγ. TZDs also inhibit G1 to S cell cycle progression. Furthermore, silencing cyclin D3 by RNA interference inhibits S phase entry and sensitizes breast cancer cells to TRAIL, indicating a key role for cyclin D3 repression in these events. G1 cell cycle arrest sensitizes breast cancer cells to TRAIL at least in part by reducing levels of the antiapoptotic protein survivin: ectopic expression of survivin partially suppresses apoptosis induced by TRAIL and TZDs. We also demonstrate for the first time that TZDs promote TRAIL-induced apoptosis of breast cancer in vivo, suggesting that this combination may be an effective therapy for cancer.

Original languageEnglish
Pages (from-to)6742-6751
Number of pages10
JournalJournal of Biological Chemistry
Volume280
Issue number8
DOIs
Publication statusPublished - 2005 Feb 25

Fingerprint

Cyclin D3
Peroxisome Proliferator-Activated Receptors
Cell Cycle Checkpoints
Cells
Apoptosis
Breast Neoplasms
Neoplasms
Cyclin D
G1 Phase Cell Cycle Checkpoints
Proteins
Caspases
RNA Interference
S Phase
Cell Cycle
Breast
Tumor Necrosis Factor-alpha
Epithelial Cells
Ligands
Chemical activation
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lu, Meiling ; Kwan, Toni ; Yu, Chunjiang ; Chen, Feng ; Freedman, Bethany ; Schafer, Jennifer M. ; Lee, Eun Jig ; Jameson, J. Larry ; Jordan, V. Craig ; Cryns, Vincent L. / Peroxisome proliferator-activated receptor γ agonists promote TRAIL-induced apoptosis by reducing survivin levels via cyclin D3 repression and cell cycle arrest. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 8. pp. 6742-6751.
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abstract = "Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapy that preferentially induces apoptosis in cancer cells. However, many neoplasms are resistant to TRAIL by mechanisms that are poorly understood. Here we demonstrate that human breast cancer cells, but not normal mammary epithelial cells, are dramatically sensitized to TRAIL-induced apoptosis and caspase activation by peroxisome proliferator-activated receptor γ (PPARγ) agonists of the thiazolidinedione (TZD) class. Although TZDs do not significantly alter the expression of components of the TRAIL signaling pathway, they profoundly reduce protein levels of cyclin D3, but not other D-type cyclins, by decreasing cyclin D3 mRNA levels and by inducing its proteasomal degradation. Importantly, both TRAIL sensitization and reduction in cyclin D3 protein levels induced by TZDs are likely PPARγ-independent because a dominant negative mutant of PPARγ did not antagonize these effects of TZDs, nor were they affected by the expression levels of PPARγ. TZDs also inhibit G1 to S cell cycle progression. Furthermore, silencing cyclin D3 by RNA interference inhibits S phase entry and sensitizes breast cancer cells to TRAIL, indicating a key role for cyclin D3 repression in these events. G1 cell cycle arrest sensitizes breast cancer cells to TRAIL at least in part by reducing levels of the antiapoptotic protein survivin: ectopic expression of survivin partially suppresses apoptosis induced by TRAIL and TZDs. We also demonstrate for the first time that TZDs promote TRAIL-induced apoptosis of breast cancer in vivo, suggesting that this combination may be an effective therapy for cancer.",
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Peroxisome proliferator-activated receptor γ agonists promote TRAIL-induced apoptosis by reducing survivin levels via cyclin D3 repression and cell cycle arrest. / Lu, Meiling; Kwan, Toni; Yu, Chunjiang; Chen, Feng; Freedman, Bethany; Schafer, Jennifer M.; Lee, Eun Jig; Jameson, J. Larry; Jordan, V. Craig; Cryns, Vincent L.

In: Journal of Biological Chemistry, Vol. 280, No. 8, 25.02.2005, p. 6742-6751.

Research output: Contribution to journalArticle

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T1 - Peroxisome proliferator-activated receptor γ agonists promote TRAIL-induced apoptosis by reducing survivin levels via cyclin D3 repression and cell cycle arrest

AU - Lu, Meiling

AU - Kwan, Toni

AU - Yu, Chunjiang

AU - Chen, Feng

AU - Freedman, Bethany

AU - Schafer, Jennifer M.

AU - Lee, Eun Jig

AU - Jameson, J. Larry

AU - Jordan, V. Craig

AU - Cryns, Vincent L.

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N2 - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapy that preferentially induces apoptosis in cancer cells. However, many neoplasms are resistant to TRAIL by mechanisms that are poorly understood. Here we demonstrate that human breast cancer cells, but not normal mammary epithelial cells, are dramatically sensitized to TRAIL-induced apoptosis and caspase activation by peroxisome proliferator-activated receptor γ (PPARγ) agonists of the thiazolidinedione (TZD) class. Although TZDs do not significantly alter the expression of components of the TRAIL signaling pathway, they profoundly reduce protein levels of cyclin D3, but not other D-type cyclins, by decreasing cyclin D3 mRNA levels and by inducing its proteasomal degradation. Importantly, both TRAIL sensitization and reduction in cyclin D3 protein levels induced by TZDs are likely PPARγ-independent because a dominant negative mutant of PPARγ did not antagonize these effects of TZDs, nor were they affected by the expression levels of PPARγ. TZDs also inhibit G1 to S cell cycle progression. Furthermore, silencing cyclin D3 by RNA interference inhibits S phase entry and sensitizes breast cancer cells to TRAIL, indicating a key role for cyclin D3 repression in these events. G1 cell cycle arrest sensitizes breast cancer cells to TRAIL at least in part by reducing levels of the antiapoptotic protein survivin: ectopic expression of survivin partially suppresses apoptosis induced by TRAIL and TZDs. We also demonstrate for the first time that TZDs promote TRAIL-induced apoptosis of breast cancer in vivo, suggesting that this combination may be an effective therapy for cancer.

AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapy that preferentially induces apoptosis in cancer cells. However, many neoplasms are resistant to TRAIL by mechanisms that are poorly understood. Here we demonstrate that human breast cancer cells, but not normal mammary epithelial cells, are dramatically sensitized to TRAIL-induced apoptosis and caspase activation by peroxisome proliferator-activated receptor γ (PPARγ) agonists of the thiazolidinedione (TZD) class. Although TZDs do not significantly alter the expression of components of the TRAIL signaling pathway, they profoundly reduce protein levels of cyclin D3, but not other D-type cyclins, by decreasing cyclin D3 mRNA levels and by inducing its proteasomal degradation. Importantly, both TRAIL sensitization and reduction in cyclin D3 protein levels induced by TZDs are likely PPARγ-independent because a dominant negative mutant of PPARγ did not antagonize these effects of TZDs, nor were they affected by the expression levels of PPARγ. TZDs also inhibit G1 to S cell cycle progression. Furthermore, silencing cyclin D3 by RNA interference inhibits S phase entry and sensitizes breast cancer cells to TRAIL, indicating a key role for cyclin D3 repression in these events. G1 cell cycle arrest sensitizes breast cancer cells to TRAIL at least in part by reducing levels of the antiapoptotic protein survivin: ectopic expression of survivin partially suppresses apoptosis induced by TRAIL and TZDs. We also demonstrate for the first time that TZDs promote TRAIL-induced apoptosis of breast cancer in vivo, suggesting that this combination may be an effective therapy for cancer.

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