TY - JOUR
T1 - Pharmacological separation of the expression of tissue transglutaminase and apoptosis after chemotherapeutic treatment of HepG2 cells
AU - Uray, I. P.
AU - Davies, P. J.A.
AU - Fésús, L.
PY - 2001
Y1 - 2001
N2 - Chemotherapeutic drugs are known to eliminate cancer cells by inducing apoptosis. Tissue transglutaminase (tTG), a frequent player in apoptotic processes, is markedly induced in drug-resistant cancer cells. To better understand the action of apoptosis-inducing drugs, our study elucidates changes in the expression of tTG in the early phase of cell death, before the downstream events of apoptosis. We demonstrate that HepG2 cells uniformly induce both tTG mRNA and enzyme activity upon treatment with cisplatin, doxorubicin, and bleomycin, chemotherapeutic agents with different modes of action. The expression of fas ligand, caspase3 and baxα changes differentially or remain unaffected, tTG expression did not change significantly after administration of either the peroxisome proliferator activated receptor-α agonist WY14643 or the retinoid X receptor-specific analog LG 100268. However, both compounds blocked drug-induced tTG induction without affecting the extent of cell death. The pleiotropic cytokine interleukin-6 effectively rescued hepatoma cells from apoptosis while tTG induction still took place, along with the induction of antiapoptotic transcripts bcl-XL, gp130, and her2/neu. These results suggest that the induction of tTG, although present in drug-induced apoptosis, is pharmacologically dissociable from the early, initiating events of apoptosis. Blocking the induction of tTG during drug-induced cell death may alleviate limiting side effects of anticancer agents, including fibrosis and neuropathies.
AB - Chemotherapeutic drugs are known to eliminate cancer cells by inducing apoptosis. Tissue transglutaminase (tTG), a frequent player in apoptotic processes, is markedly induced in drug-resistant cancer cells. To better understand the action of apoptosis-inducing drugs, our study elucidates changes in the expression of tTG in the early phase of cell death, before the downstream events of apoptosis. We demonstrate that HepG2 cells uniformly induce both tTG mRNA and enzyme activity upon treatment with cisplatin, doxorubicin, and bleomycin, chemotherapeutic agents with different modes of action. The expression of fas ligand, caspase3 and baxα changes differentially or remain unaffected, tTG expression did not change significantly after administration of either the peroxisome proliferator activated receptor-α agonist WY14643 or the retinoid X receptor-specific analog LG 100268. However, both compounds blocked drug-induced tTG induction without affecting the extent of cell death. The pleiotropic cytokine interleukin-6 effectively rescued hepatoma cells from apoptosis while tTG induction still took place, along with the induction of antiapoptotic transcripts bcl-XL, gp130, and her2/neu. These results suggest that the induction of tTG, although present in drug-induced apoptosis, is pharmacologically dissociable from the early, initiating events of apoptosis. Blocking the induction of tTG during drug-induced cell death may alleviate limiting side effects of anticancer agents, including fibrosis and neuropathies.
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UR - http://www.scopus.com/inward/citedby.url?scp=0034986420&partnerID=8YFLogxK
U2 - 10.1124/mol.59.6.1388
DO - 10.1124/mol.59.6.1388
M3 - Article
C2 - 11353797
AN - SCOPUS:0034986420
SN - 0026-895X
VL - 59
SP - 1388
EP - 1394
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 6
ER -