Peroxisome proliferator-activated receptor gamma agonists promote TRAIL-induced apoptosis by reducing survivin levels via cyclin D3 repression and cell cycle arrest.
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 gamma (PPARgamma) 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 PPARgamma-independent because a dominant negative mutant of PPARgamma did not antagonize these effects of TZDs, nor were they affected by the expression levels of PPARgamma. TZDs also inhibit G(1) 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. G(1) cell cycle arrest sensitizes breast cancer cells to TRAIL at least in part by reducing levels of the anti-apoptotic 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.
Lu
Meiling
M
Cell Death Regulation Laboratory, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Kwan
Toni
T
Yu
Chunjiang
C
Chen
Feng
F
Freedman
Bethany
B
Schafer
Jennifer M
JM
Lee
Eun-Jig
EJ
Jameson
J Larry
JL
Jordan
V Craig
VC
Cryns
Vincent L
VL
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D056743:Cyclin D3; D016213:Cyclins / Q000187:drug effects* / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; D045162:Thiazolidinediones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; C534696:CCND3 protein, human; D056743:Cyclin D3; D016213:Cyclins; D051034:Inhibitor of Apoptosis Proteins; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D047495:PPAR gamma; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; C089946:2,4-thiazolidinedione; D020169:Caspases