TY - JOUR
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.
PY - 2005/2/25
Y1 - 2005/2/25
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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U2 - 10.1074/jbc.M411519200
DO - 10.1074/jbc.M411519200
M3 - Article
C2 - 15569667
AN - SCOPUS:20044372348
SN - 0021-9258
VL - 280
SP - 6742
EP - 6751
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 8
ER -