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Signaling and Regulation

The Phosphoinositide 3-Kinase/AKT1 Pathway Involvement in Drug and All-Trans-Retinoic Acid Resistance of Leukemia Cells¹

¹ Dipartimento di Morfologia ed Embriologia and ² Interdisciplinary Center for the Study of Inflammation, Università di Ferrara, Ferrara, Italy;
³ Istituto per i Trapianti d'Organo e l'Immunocitologia del C.N.R., Sezione di Bologna, Bologna, Italy;
⁴ Servizio di Immunoematologia e Trasfusionale, Policlinico S. Orsola, Bologna, Italy;
⁵ Dipartimento di Morfologia Umana Normale, Università di Trieste, Trieste, Italy;
⁶ Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA;
⁷ Dipartimento di Genetica Medica, Università Cattolica del S. Cuore, Rome, Italy; and
⁸ Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Università di Bologna, Bologna, Italy

Requests for reprints: Alberto M. Martelli, Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Università di Bologna, via Irnerio 48, 40126 Bologna, Italy. Phone: 39-051-243103; Fax: 39-051-2091695. E-mail: amartell{at}biocfarm.unibo.it

Disruption of the apoptotic pathways may account for resistance to chemotherapy and treatment failures in human neoplastic disease. To further evaluate this issue, we isolated a HL-60 cell clone highly resistant to several drugs inducing apoptosis and to the differentiating chemical all-trans-retinoic acid (ATRA). The resistant clone displayed an activated phosphoinositide 3-kinase (PI3K)/AKT1 pathway, with levels of phosphatidylinositol (3,4,5) trisphosphate higher than the parental cells and increased levels of both Thr 308 and Ser 473 phosphorylated AKT1. In vitro AKT1 activity was elevated in resistant cells, whereas treatment of the resistant cell clone with two inhibitors of PI3K, wortmannin or Ly294002, strongly reduced phosphatidylinositol (3,4,5) trisphosphate levels and AKT1 activity. The inhibitors reversed resistance to drugs. Resistant cells overexpressing either dominant negative PI3K or dominant negative AKT1 became sensitive to drugs and ATRA. Conversely, if parental HL-60 cells were forced to overexpress an activated AKT1, they became resistant to apoptotic inducers and ATRA. There was a tight relationship between the activation of the PI3K/AKT1 axis and the expression of c-IAP1 and c-IAP2 proteins. Activation of the PI3K/AKT1 axis in resistant cells was dependent on enhanced tyrosine phosphorylation of the p85 regulatory subunit of PI3K, conceivably due to an autocrine insulin-like growth factor-I production. Our findings suggest that an up-regulation of the PI3K/AKT1 pathway might be one of the survival mechanisms responsible for the onset of resistance to chemotherapeutic and differentiating therapy in patients with acute leukemia.

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