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Phosphoinositide 3‐kinase/Akt involvement in arsenic trioxide resistance of human leukemia cells
Author(s) -
Tabellini Giovanna,
Cappellini Alessandra,
Tazzari Pier Luigi,
Falà Federica,
Billi Anna Maria,
Manzoli Lucia,
Cocco Lucio,
Martelli Alberto M.
Publication year - 2005
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.20153
Subject(s) - wortmannin , protein kinase b , ly294002 , pi3k/akt/mtor pathway , k562 cells , phosphoinositide 3 kinase , hl60 , cancer research , biology , arsenic trioxide , apoptosis , microbiology and biotechnology , chemistry , signal transduction , biochemistry
The purpose of this study was to evaluate the possible involvement of the phosphoinositide 3‐kinase (PI3K)/Akt survival pathway in determining resistance to arsenic trioxide (As 2 O 3 )‐induced apoptosis. We employed a HL60 cell clone (HL60AR) with a constitutively active PI3K/Akt survival pathway, as well as U937 and K562 cells. In addition, we used parental (PT) HL60 cells overexpressing a constitutively active Akt. Selective pharmacological inhibitors of the PI3K/Akt axis (LY294002, wortmannin) were employed to influence the sensitivity to As 2 O 3 . While HL60PT cells were sensitive to 2.5 μM As 2 O 3 and died of apoptosis, HL60AR cells were resistant up to 5 μM As 2 O 3 . Treatment with either LY294002 or wortmannin lowered resistance of HL60AR cells to As 2 O 3 . Also in U937 and K562 cells, inhibitors of the PI3K/Akt axis caused a decrease in As 2 O 3 resistance. Overexpression of constitutively active Akt in HL60PT cells caused the induction of resistance to 2.5 μM As 2 O 3 . Conversely, forced expression of a dominant negative Akt in HL60AR cells resulted in a decrease in As 2 O 3 resistance. Moreover, HL60 cell resistance to 2.5 μM As 2 O 3 could be significantly reduced by incubation with SN50, a peptide inhibitor selective for the NF‐κB transcription factor. Taken together our findings suggest that a constitutive activation of the PI3K/Akt pathway, which is increasingly detected in some types of acute myeloid leukemia, may contribute to As 2 O 3 resistance, most likely through NF‐κB activation. Selective pharmacological inhibitors of this survival pathway, as well as of NF‐κB, might be usefully employed in the future to reverse resistance to this treatment. © 2004 Wiley‐Liss, Inc.