DOI: 10.1182/blood-2002-02-0539. Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cδ

Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cδ

10.1182/blood-2002-02-0539

Crossref journal-article

American Society of Hematology

Blood (234)

Abstract

In the present study we analyzed the role of phophatidylinositol-3 kinase (PI-3K) in B chronic lymphocytic leukemia (B-CLL) cells. PI-3K is activated by many stimuli and is linked to several different signaling pathways. We demonstrated that inhibition of PI-3K by a specific inhibitor, LY294002, induced apoptosis in B-CLL cells in vitro. This effect was specific for the inhibition of PI-3K because inhibition of other signaling pathways such as extracellular signaling–regulated kinase (ERK), p38, or p70S6 kinase did not affect spontaneous apoptosis. Furthermore, PI-3K was constitutively activated in freshly isolated B-CLL cells. Corresponding to enhanced apoptosis, LY294002 down-regulated expression of the antiapoptotic proteins X-linked inhibitor of apoptosis protein (XIAP) and Mcl-1. Next, we investigated which factors downstream of PI-3K were activated in B-CLL cells. We demonstrated that protein kinase B/Akt is expressed in all tested CLL samples but no activation of Akt was detected. In contrast, we observed a constitutive activation of protein kinase Cδ (PKCδ) in freshly isolated B-CLL cells. PKCδ is linked to PI-3K and is phosphorylated at Thr505 in response to PI-3K activation. We further demonstrated that tyrosine phosphorylation and activity of PKCδ were dependent on PI-3K activity in B-CLL cells. Inhibition of PKCδ by the specific inhibitor Rottlerin strikingly enhanced apoptosis. In contrast, peripheral blood B cells of healthy donors were resistant to inhibition of PI-3K or PKCδ. We conclude that activated PI-3K might be important in the pathogenesis of B-CLL, and survival signals might be mediated via PKCδ. Therefore, inhibition of PI-3K or PKCδ may be an innovative approach to treat B-CLL.

Bibliography

Ringshausen, I., Schneller, F., Bogner, C., Hipp, S., Duyster, J., Peschel, C., & Decker, T. (2002). Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase CÎ´. Blood, 100(10), 3741â3748.

Authors 7

Ingo Ringshausen (first)
Folker Schneller (additional)
Christian Bogner (additional)
Susanne Hipp (additional)
Justus Duyster (additional)
Christian Peschel (additional)
Thomas Decker (additional)

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Dates

Type	When
Created	22 years, 10 months ago (Oct. 30, 2002, 2:43 p.m.)
Deposited	2 years, 4 months ago (April 24, 2023, 3:38 p.m.)
Indexed	3 days, 7 hours ago (Sept. 3, 2025, 6:07 a.m.)
Issued	22 years, 9 months ago (Nov. 15, 2002)
Published	22 years, 9 months ago (Nov. 15, 2002)
Published Print	22 years, 9 months ago (Nov. 15, 2002)

Funders 0

None

BibTeX

@article{Ringshausen_2002, title={Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cδ}, volume={100}, ISSN={0006-4971}, url={http://dx.doi.org/10.1182/blood-2002-02-0539}, DOI={10.1182/blood-2002-02-0539}, number={10}, journal={Blood}, publisher={American Society of Hematology}, author={Ringshausen, Ingo and Schneller, Folker and Bogner, Christian and Hipp, Susanne and Duyster, Justus and Peschel, Christian and Decker, Thomas}, year={2002}, month=nov, pages={3741–3748} }

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  "abstract": "<jats:p>In the present study we analyzed the role of phophatidylinositol-3 kinase (PI-3K) in B chronic lymphocytic leukemia (B-CLL) cells. PI-3K is activated by many stimuli and is linked to several different signaling pathways. We demonstrated that inhibition of PI-3K by a specific inhibitor, LY294002, induced apoptosis in B-CLL cells in vitro. This effect was specific for the inhibition of PI-3K because inhibition of other signaling pathways such as extracellular signaling\u2013regulated kinase (ERK), p38, or p70S6 kinase did not affect spontaneous apoptosis. Furthermore, PI-3K was constitutively activated in freshly isolated B-CLL cells. Corresponding to enhanced apoptosis, LY294002 down-regulated expression of the antiapoptotic proteins X-linked inhibitor of apoptosis protein (XIAP) and Mcl-1. Next, we investigated which factors downstream of PI-3K were activated in B-CLL cells. We demonstrated that protein kinase B/Akt is expressed in all tested CLL samples but no activation of Akt was detected. In contrast, we observed a constitutive activation of protein kinase C\u03b4 (PKC\u03b4) in freshly isolated B-CLL cells. PKC\u03b4 is linked to PI-3K and is phosphorylated at Thr505 in response to PI-3K activation. We further demonstrated that tyrosine phosphorylation and activity of PKC\u03b4 were dependent on PI-3K activity in B-CLL cells. Inhibition of PKC\u03b4 by the specific inhibitor Rottlerin strikingly enhanced apoptosis. In contrast, peripheral blood B cells of healthy donors were resistant to inhibition of PI-3K or PKC\u03b4. We conclude that activated PI-3K might be important in the pathogenesis of B-CLL, and survival signals might be mediated via PKC\u03b4. Therefore, inhibition of PI-3K or PKC\u03b4 may be an innovative approach to treat B-CLL.</jats:p>",
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