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The role of the proteasome in apoptosis induced by anthracycline anticancer agents
Ken-Ichi Kiyomiya1, Masaru Kurebe, Hiroshi Nakagawa
1Laboratory of Toxicology, Graduate School of Veterinary Medicine, Osaka Prefecture University, Sakai 599-8531, Japan. kiyomiya@vet.osakafu-u.ac.jp
Abstract:
To elucidate the involvement of proteasome inhibition in apoptosis induced by anthracycline anticancer agents, we investigated the interaction between the proteasome and anthracycline anticancer agents, and the function of the proteasome in apoptosis. Exposure of L1210 mouse lymphocytic leukemia cells to adriamycin (ADM) or 4'-O-tetrahydropyranyladriamycin (THP) resulted in apoptosis in a dose-dependent manner: 5 microM ADM and 0.5 microM THP induced apoptosis efficiently, but the effects of 10 microM ADM and 5 microM THP were markedly decreased or completely absent. Carbobenzoxy-leucyl-leucyl-leucinal (Z-LLLal), a specific proteasome inhibitor, also induced dose-dependent apoptosis of the cells. The inhibitory effect of THP on chymotrypsin-like protease activity of proteasomes purified from the cytosol of L1210 cells was stronger than that of ADM. Both of these agents showed reversible non-competitive inhibitory effects. The intracellular content of ubiquitinated protein increased in ADM-, THP- or Z-LLLal-treated L1210 cells during apoptosis. These results suggested that anthracycline anticancer agents induce apoptosis by interacting, at least in part, with proteasomes.
Insights
Anthracycline anticancer agents, like adriamycin, induce apoptosis by inhibiting proteasomes. This proteasome inhibition increases ubiquitinated proteins, leading to programmed cell death in leukemia cells.
Area of Science:
- * Pharmacology
- * Molecular Biology
- * Cancer Research
Background:
- * Anthracycline anticancer agents are widely used in chemotherapy.
- * The precise mechanisms by which these agents induce apoptosis are not fully understood.
- * Proteasomes play a critical role in cellular protein degradation and apoptosis regulation.
Purpose of the Study:
- * To investigate the role of proteasome inhibition in anthracycline-induced apoptosis.
- * To examine the interaction between anthracycline anticancer agents and proteasomes.
- * To understand the functional consequences of proteasome interaction in apoptosis.
Main Methods:
- * L1210 mouse lymphocytic leukemia cells were exposed to varying concentrations of adriamycin (ADM) and 4'-O-tetrahydropyranyladriamycin (THP).
- * The effect of a specific proteasome inhibitor, carbobenzoxy-leucyl-leucyl-leucinal (Z-LLLal), on apoptosis was assessed.
- * Proteasome activity (chymotrypsin-like protease activity) and intracellular ubiquitinated protein levels were measured.
Main Results:
- * ADM and THP induced apoptosis in a dose-dependent manner, with optimal effects at lower concentrations.
- * The proteasome inhibitor Z-LLLal also induced apoptosis.
- * THP exhibited a stronger inhibitory effect on proteasome activity than ADM.
- * Both agents demonstrated reversible, non-competitive inhibition of proteasomes.
- * Treatment with ADM, THP, or Z-LLLal led to an increase in intracellular ubiquitinated protein during apoptosis.
Conclusions:
- * Anthracycline anticancer agents, including ADM and THP, induce apoptosis through mechanisms involving proteasome inhibition.
- * The interaction with proteasomes and subsequent increase in ubiquitinated proteins contribute to the apoptotic effect.
- * These findings elucidate a key molecular mechanism of anthracycline anticancer drugs.