Modulation of the activity of calcium-activated neutral proteases (calpains) in chronic lymphocytic leukemia (B-CLL) cells

被引:45
作者
Witkowski, JM
Zmuda-Trzebiatowska, E
Swiercz, JM
Cichorek, M
Ciepluch, H
Lewandowski, K
Bryl, E
Hellmann, A
机构
[1] Med Univ Gdansk, Dept Pathophysiol, PL-80211 Gdansk, Poland
[2] Med Univ Gdansk, Dept Embryol, PL-80211 Gdansk, Poland
[3] Med Univ Gdansk, Dept Hematol, PL-80211 Gdansk, Poland
[4] Med Univ Gdansk, Dept Immunopathol, PL-80211 Gdansk, Poland
关键词
D O I
10.1182/blood-2001-11-0073
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Decreased susceptibility to apoptosis and impaired proliferative control are thought to be responsible for prolonged life span and accumulation of chronic lymphocytic leukemia (B-CLL) cells. The activity of calpains (calcium-dependent, neutral proteases, active in the cells responding to signals inducing a rise of cytoplasmic Ca++) is involved in the regulation of apoptosis of some cell types by interaction with caspase-3. This work verifies the hypothesis of the abnormal activity of calpains and its role in reduced apoptosis of the B-CLL cells. Casein zymography, reverse transcriptase-polymerase chain reaction, and Western blotting were used for identification and quantification of the activity and expression of calpains in B-CLL cells and purified normal B lymphocytes. The activity and expression of mu-calpain (requiring micromolar Ca++ for activation) are significantly higher in the leukemic than in nonmalignant cells. Contrarily, the activity and expression of m-calpain (requiring millimolar Ca++) as well as the expression of calpastatin (an endogenous inhibitor of calpains) are unchanged or reduced in the B-CLL lymphocytes. Correspondingly, the activity of caspase-3 is many times lower in the B-CLL cells than in normal B lymphocytes. Inhibition of overexpressed mu-calpain in living B-CLL cells in vitro results in doubling of the proportion of the cells undergoing spontaneous apoptosis. This observation suggests a possible role for calpains in longer survival of the B-CLL cells and may open new therapeutic possibilities.
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页码:1802 / 1809
页数:8
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