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PTEN Reverses MDM2-mediated Chemotherapy Resistance by Interacting with p53 in Acute Lymphoblastic Leukemia Cells¹

Division of Pediatric Hematology/Oncology/Bone Marrow Transplantation, Emory University School of Medicine, Atlanta, Georgia 30322

The tumor suppressor PTEN has been associated with the cellular localization of MDM2 in regulation of apoptosis through inhibiting PI3k/Akt signaling. To investigate whether expression of PTEN is involved in MDM2-mediated chemoresistance, we examined a set of acute lymphoblastic leukemia (ALL) cell lines for the expression of PTEN and sensitivity to doxorubicin. Testing 9 ALL cell lines selected for wild-type p53 phenotype and uniformly high levels of MDM2 expression, we initially demonstrated that cell lines with high levels of PTEN expression were sensitive to doxorubicin, whereas lines lacking PTEN expression were generally resistant. Forced expression of PTEN in a PTEN-negative and doxorubicin-resistant ALL line (EU-1) resulted in decreased cell growth and enhanced sensitivity to doxorubicin. Examining the cellular localization of MDM2, we confirmed that the majority of MDM2 is localized in the nucleus in PTEN-negative doxorubicin-sensitive ALL cells, whereas MDM2 is expressed predominantly in the cytoplasm in either PTEN-positive or PTEN-transfected cells. Furthermore, by coimmunoprecipitaton and cotransfection assays, we found that PTEN physically binds p53 in vitro as well as in vivo. Binding of PTEN to p53 attenuated MDM2-mediated p53 inhibition. These results suggest that PTEN inhibits MDM2 and protects p53 through both p13k/Akt-dependent and -independent pathways. Furthermore, loss of PTEN can result in resistance to apoptosis by activating MDM2-mediated antiapoptotic mechanism.

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