Inhibition of class I phosphoinositide 3-kinase activity impairs proliferation and triggers apoptosis in acute promyelocytic leukemia without affecting atra-induced differentiation.
We have investigated the role of phosphoinositide 3-kinases (PI3Ks) in the in vitro pathophysiology of acute promyelocytic leukemia (APL) and in the response to treatment with all-trans-retinoic-acid (ATRA), utilizing a range of novel inhibitors that target individual or all catalytic class I isoforms of PI3K (p110alpha, p110beta, p110delta, and p110gamma). ATRA-induced phosphorylation of the Akt kinase and ribosomal S6 protein in APL cells was sensitive to class I PI3K, and p110beta or p110delta inhibitors, and to the mammalian target of rapamycin (mTOR) inhibitor rapamycin. In primary APL, inhibition of p110beta or p110delta triggered apoptosis in the absence or presence of ATRA. Class I PI3K inhibition could also reverse ATRA-induced protection of these cells against doxorubicin and arsenic trioxide, correlating with impaired induction of the antiapoptotic MCL-1 protein. The differentiation-inducing effects of ATRA were not dependent on class I PI3K/mTOR. In summary, class I PI3K signaling, mediated by p110beta and p110delta, plays an important role in basal and ATRA-induced cell survival mechanisms in APL. Addition of PI3K inhibitors to induction treatment regimens may provide therapeutic benefit.
Billottet
Clotilde
C
Centre for Cell Signalling, Queen Mary University of London, Institute of Cancer, Barts and The London School of Medicine, John Vane Science Centre University College London, London, United Kingdom.
Banerjee
Lalita
L
Vanhaesebroeck
Bart
B
Khwaja
Asim
A
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D048708:Cell Growth Processes; D006801:Humans; D007527:Isoenzymes; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013379:Substrate Specificity; D058570:TOR Serine-Threonine Kinases; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D007527:Isoenzymes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014212:Tretinoin; C546842:MTOR protein, human