Positive Effects of PI3K/Akt Signaling Inhibition on PTEN and P53 inPrevention of Acute Lymphoblastic Leukemia Tumor Cells

The PI3K/Akt signaling pathway regulates cell growth, proliferation and viability inhematopoietic cells. This pathway always dysregulates in acute lymphoblastic leukemia (ALL).PTEN and P53 are tumor suppressor genes correlated with PI3K/Akt signaling pathway, and bothhave a tight link in regulation of cell proliferation and cell death. In this study, we investigatedthe effects of dual targeting of PI3K/Akt pathway by combined inhibition with nvp-BKM-120(PI3K inhibitor) and MK-2206 (Akt inhibitor) in relation with PTEN and P53 on apoptosis andproliferation of leukemia cells. Both T and B ALL cell lines were treated with both inhibitors alone or in combinationwith each other, and induction of apoptosis and inhibition of proliferation were evaluated byflow cytometry. Expression levels of PTEN as well as p53 mRNA and protein were measured byreal-time qRT-PCR and western blot, respectively. We indicated that both inhibitors (BKM-120 and MK-2206) decreased cell viability andincreased cytotoxicity in leukemia cells. Reduction in Akt phosphorylation increased PTEN andp53 mRNA and p53 protein level (in PTEN positive versus PTEN negative cell lines). Additionally,both inhibitors, particularly in combination with each other, increased apoptosis (evaluatedwith Annexin V and caspase 3) and reduced proliferation (Ki67 expression) in leukemia cells.However, administration of IL7 downregulated PTEN and P53 mRNA expression and rescuedcancer cells following inhibition of BKM-120 and MK-2206. This investigation suggested that inhibition of Akt and PI3K could be helpful inleukemia treatment.