PMID- 15193543
OWN - NLM
STAT- MEDLINE
DCOM- 20050114
LR  - 20061115
IS  - 8756-3282 (Print)
IS  - 1873-2763 (Linking)
VI  - 34
IP  - 6
DP  - 2004 Jun
TI  - Thapsigargin potentiates TRAIL-induced apoptosis in giant cell tumor of bone.
PG  - 971-81
AB  - TNF-related apoptosis-inducing ligand (TRAIL) is capable of causing apoptosis in 
      tumor cells but not in normal cells; however, it has been shown that certain 
      types of tumor cells are resistant to TRAIL-induced apoptosis. In this study, we 
      examined the potentiation of TRAIL-induced apoptosis in the stromal-like tumor 
      cells of giant cell tumor of bone (GCT). We show that both mRNA and protein of 
      TRAIL receptors-death receptors (DR4, DR5) and decoy receptors (DcR1, DcR2) are 
      present in GCT stromal tumor cells. However, the expression profiles in all GCT 
      clones tested do not readily correlate with their differential sensitivity to 
      TRAIL. To this end, we selected thapsigargin (TG), an agent known to cause 
      perturbations in intracellular Ca(2+) homeostasis to enhance the apoptotic action 
      of TRAIL. When added alone, neither TRAIL nor TG induces a therapeutically 
      important magnitude of cell death in GCT tumor cells. Interdependently, scheduled 
      treatment of the cultures with TG followed by subsequent addition of TRAIL 
      resulted in a significant synergistic apoptotic activity, while in contrast, no 
      obvious augmentation was seen when TRAIL was added before TG. This effect was in 
      accord with our observation that TG predominantly up-regulated both mRNA and 
      protein expression of DR5, as well as DR4 mRNA while down-regulating DcR1 protein 
      in GCT stromal-like tumor cells. Taken together, our findings suggest that TG is 
      able to sensitize tumor cells of GCT to TRAIL-induced cell death, perhaps in part 
      through up-regulating the death receptor DR5 and down-regulating the decoy 
      receptor DcR1. These findings provide an additional insight into the design of 
      new treatment modalities for patients suffering from GCT.
FAU - Huang, Lin
AU  - Huang L
AD  - Department of Orthopaedics and Traumatology, the Chinese University of Hong Kong, 
      Shatin, N.T., Hongkong SAR, China.
FAU - Xu, Jiake
AU  - Xu J
FAU - Li, Karen
AU  - Li K
FAU - Zheng, Ming H
AU  - Zheng MH
FAU - Kumta, Shekhar-M
AU  - Kumta SM
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Bone
JT  - Bone
JID - 8504048
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNFSF10 protein, human)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 67526-95-8 (Thapsigargin)
SB  - IM
MH  - Apoptosis/*drug effects/physiology
MH  - Apoptosis Regulatory Proteins
MH  - Bone Neoplasms/*drug therapy/metabolism
MH  - Cell Survival/drug effects/physiology
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Giant Cell Tumor of Bone/*drug therapy/metabolism
MH  - Humans
MH  - Membrane Glycoproteins/biosynthesis/*pharmacology/therapeutic use
MH  - Receptors, Tumor Necrosis Factor/biosynthesis
MH  - TNF-Related Apoptosis-Inducing Ligand
MH  - Thapsigargin/*pharmacology/therapeutic use
MH  - Tumor Cells, Cultured
MH  - Tumor Necrosis Factor-alpha/biosynthesis/*pharmacology/therapeutic use
EDAT- 2004/06/15 05:00
MHDA- 2005/01/15 09:00
CRDT- 2004/06/15 05:00
PHST- 2003/09/02 00:00 [received]
PHST- 2004/01/16 00:00 [revised]
PHST- 2004/02/03 00:00 [accepted]
PHST- 2004/06/15 05:00 [pubmed]
PHST- 2005/01/15 09:00 [medline]
PHST- 2004/06/15 05:00 [entrez]
AID - S8756328204000699 [pii]
AID - 10.1016/j.bone.2004.02.005 [doi]
PST - ppublish
SO  - Bone. 2004 Jun;34(6):971-81. doi: 10.1016/j.bone.2004.02.005.