Cell adhesion regulates CDC25A expression and proliferation in acute myeloid leukemia.
The effects of cell adhesion on leukemia cell proliferation remain poorly documented and somehow controversial. In this work, we investigated the effect of adhesion to fibronectin on the proliferation of acute myeloid leukemia (AML) cell lines (U937 and KG1a) and CD34+ normal or leukemic primary cells. We observed an increased rate of proliferation of AML cells when adhered to fibronectin, concomitant with accelerated S-phase entry and accumulation of CDC25A. Conversely, normal CD34+ cell proliferation was decreased by adhesion to fibronectin with a concomitant drop in CDC25A expression. Importantly, we showed that both small interfering RNA (siRNA)-mediated CDC25A down-regulation and a recently developed CDC25 pharmacologic inhibitor impaired this adhesion-dependent proliferation, establishing a functional link between CDC25A accumulation and adhesion-dependent proliferation in leukemic cells. CDC25A accumulation was found only slightly dependent on transcriptional regulation and essentially due to modifications of the proteasomal degradation of the protein as shown using proteasome inhibitors and reverse transcription-PCR. Interestingly, CDC25A regulation was Chk1 dependent in these cells as suggested by siRNA-mediated down-regulation of this protein. Finally, we identified activation of the phosphatidylinositol 3-kinase/Akt pathway as an adhesion-dependent regulation mechanism of CDC25A protein expression. Altogether, our data show that in leukemic cells adhesion to fibronectin increases CDC25A expression through proteasome- and Chk1-dependent mechanisms, resulting in enhanced proliferation. They also suggest that these adhesion-dependent proliferation properties of hematopoietic cells may be modified during leukemogenesis.
Fernandez-Vidal
Anne
A
Centre de Physiopathologie Toulouse-Purpan, Institut National de la Sante et de la Recherche Medicale U563-IFR30, Département "Oncogenèse et Signalisation dans les cellules hématopoïétiques," Purpan, Toulouse, France.
Ysebaert
Loïc
L
Didier
Christine
C
Betous
Remy
R
De Toni
Fabienne
F
Prade-Houdellier
Naïs
N
Demur
Cécile
C
Contour-Galcéra
Marie-Odile
MO
Prévost
Grégoire P
GP
Ducommun
Bernard
B
Payrastre
Bernard
B
Racaud-Sultan
Claire
C
Manenti
Stéphane
S
D000208:Acute Disease; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D000071877:Checkpoint Kinase 1; D005353:Fibronectins / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D058570:TOR Serine-Threonine Kinases; D020298:U937 Cells; D015854:Up-Regulation; D020687:cdc25 Phosphatases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
D000071877:Checkpoint Kinase 1; D005353:Fibronectins; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D011494:Protein Kinases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D020687:cdc25 Phosphatases; C546842:MTOR protein, human; C000605867:CHEK1 protein, human; C517004:CDC25A protein, human