Pharmacological Separation of the Expression of Tissue Transglutaminase and Apoptosis after Chemotherapeutic Treatment of HepG2 Cells
- 1Department of Biochemistry and Molecular Biology, University of Debrecen, Medical and Health Science Center, Faculty of Medicine, Debrecen, Hungary (I.P.U., L.F.); and 2Department of Integrative Biology and Pharmacology, University of Texas at Houston Medical School, Houston, Texas (I.P.U., P.J.A.D.)
Abstract
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.
Footnotes
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Send reprint requests to: LászlóFésüs, Department of Biochemistry and Molecular Biology, University of Debrecen, Medical and Health Science Center, Faculty of Medicine, P.O. Box 6, H-4012 Debrecen, Hungary. E-mail:fesus{at}indi.biochem.dote.hu
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This study was supported by the Hungarian National Research Fund (OTKA T-21279, T-22690, T-029672, and N-28760) and in part by National Institutes of Health Grant CA76088.
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This work was previously presented at the 6th Conference on Transglutaminases and Crosslinking Reactions; Lyon, France; 2000 Sept 15–19.
- Abbreviations:
- tTG
- tissue transglutaminase
- TG
- transglutaminase
- Cis
- cisplatin
- Dox
- doxorubicin
- Bleo
- bleomycin
- RT
- reverse transcriptase
- PCR
- polymerase chain reaction
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
- IL-6
- Interleukin-6
- PPAR
- peroxisome proliferator activated receptor
- RXR
- retinoid X receptor
- NFκB
- nuclear factor κB
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- Received October 16, 2000.
- Accepted February 28, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
