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Molecular Targets for Therapy

Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts

Leukemia volume 21, pages 427–438 (2007)Cite this article

Abstract

A high incidence of relapses following induction chemotherapy is a major hindrance to patient survival in acute myelogenous leukemia (AML). There is strong evidence that activation of the phosphoinositide 3 kinase (PI3K)/Akt signaling network plays a significant role in rendering AML blasts drug resistant. An important mechanism underlying drug resistance is represented by overexpression of membrane drug transporters such as multidrug resistance-associated protein 1 (MRP1) or 170-kDa P-glycoprotein (P-gp). Here, we present evidence that MRP1, but not P-gp, expression is under the control of the PI3K/Akt axis in AML blasts. We observed a highly significant correlation between levels of phosphorylated Akt and MRP1 expression in AML cells. Furthermore, incubation of AML blasts with wortmannin, a PI3K pharmacological inhibitor, resulted in lower levels of phosphorylated Akt, downregulated MRP1 expression, and decreased Rhodamine 123 extrusion in an in vitro functional dye efflux assay. We also demonstrate that wortmannin-dependent PI3K/Akt inhibition upregulated p53 protein levels in most AML cases, and this correlated with diminished MRP1 expression and enhanced phosphorylation of murine double minute 2 (MDM2). Taken together, these data suggest that PI3K/Akt activation may lead to the development of chemoresistance in AML blasts through a mechanism involving a p53-dependent suppression of MRP1 expression.

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Acknowledgements

This work was supported by grants from: CARISBO Foundation, Associazione Italiana Ricerca sul Cancro (AIRC Regional grants), Italian MIUR FIRB 2001, and COFIN 2005. JAM was supported by the USA Public Health Service (RO1098195).

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Authors and Affiliations

  1. Servizio di Immunoematologia e Trasfusionale, Policlinico S.Orsola-Malpighi, Bologna, Italy

    P L Tazzari, F Ricci & R Conte

  2. Dipartimento di Scienze Motorie e della Salute, Sezione di Anatomia,

    A Cappellini

  3. Università di Cassino, Cassino, Italy

    A Cappellini

  4. Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Università di Bologna, Bologna, Italy

    C Evangelisti, V Papa, L Cocco & A M Martelli

  5. Istituto di Ematologia ed Oncologia Medica Seràgnoli, Università di Bologna, Bologna, Italy

    T Grafone & G Martinelli

  6. Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, USA

    J A McCubrey

  7. ITOI-C.N.R., c/o I.O.R., Bologna, Italy

    A M Martelli

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  1. P L Tazzari
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Correspondence to A M Martelli.

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Tazzari, P., Cappellini, A., Ricci, F. et al. Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts. Leukemia 21, 427–438 (2007). https://doi.org/10.1038/sj.leu.2404523

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