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

Abstract

Purpose: The PI3K/Akt signaling pathway regulates cell growth, proliferation and viability in hematopoietic cells. This pathway always dysregulates in acute lymphoblastic leukemia (ALL). PTEN and P53 are tumor suppressor genes correlated with PI3K/Akt signaling pathway, and both have a tight link in regulation of cell proliferation and cell death. In this study, we investigated the 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 and proliferation of leukemia cells. Methods: Both T and B ALL cell lines were treated with both inhibitors alone or in combination with each other, and induction of apoptosis and inhibition of proliferation were evaluated by flow cytometry. Expression levels of PTEN as well as p53 mRNA and protein were measured by real-time qRT-PCR and western blot, respectively. Results: We indicated that both inhibitors (BKM-120 and MK-2206) decreased cell viability and increased cytotoxicity in leukemia cells. Reduction in Akt phosphorylation increased PTEN and p53 mRNA and p53 protein level (in PTEN positive versus PTEN negative cell lines). Additionally, both inhibitors, particularly in combination with each other, increased apoptosis (evaluated with Annexin V and caspase 3) and reduced proliferation (Ki67 expression) in leukemia cells. However, administration of IL7 downregulated PTEN and P53 mRNA expression and rescued cancer cells following inhibition of BKM-120 and MK-2206. Conclusion: This investigation suggested that inhibition of Akt and PI3K could be helpful in leukemia treatment.

Combined Application of Pan-AKT Inhibitor MK-2206 and BCL-2 Antagonist Venetoclax in B-Cell Precursor Acute Lymphoblastic Leukemia

“…Matching our data Simioni et al detected decreased AKT phosphorylation in SEM cells incubated with 0.5 µM MK-2206 for 30 min [ 15 ]. Han et al obtained similar results in NALM-6 cells [ 16 ] and Naderali et al observed AKT dephosphorylation in NALM-6 and REH cells [ 17 ]. However, both studies only surveyed one particular time point using a single concentration of MK-2206.…”

“…However, due to its high oncogenic potential and frequent dysregulation it remains a key target for pharmacological intervention. Regarding B-ALL only few groups investigated the effect of sole AKT inhibitors: Levy et al demonstrated that GSK690693 acted anti-proliferative and induced apoptosis [ 13 , 14 ] while three other manuscripts investigated pan-AKT inhibitor MK-2206 [ 15 , 16 , 17 ]. Both drugs induced significant anti-proliferative effects in leukemic cell lines and changes in AKT downstream protein phosphorylation.…”

“…In relapsed chronic lymphoblastic leukemia patients an overall response rate of 92% was achieved with MK-2206 in combination with bendamustine and rituximab [ 26 ], raising hopes for further investigation of other arrangements. Several preclinical studies have been conducted for T-cell ALL [ 27 , 28 , 29 , 30 ], demonstrating broad anti-proliferative activity, but data on B-ALL is sparse, especially for primary samples and combinatorial approaches [ 15 , 16 , 17 ].…”

Integrative Bioinformatics Study Reveals Tangeretin Targets and Molecular Mechanisms Against Metastatic Breast Cancer

“…A previous study showed that PI3K/Akt promotes p53 translation in cancer development (63). Inhibition of PI3K/Akt signaling leads to p53 upregulation in leukemic cancer cells (64). A recent study has reported p53 upregulation due to PI3K/Akt signaling inhibition in EMT inhibition in liver cancer cells (65).…”

Computational quantification of global effects induced by mutations and drugs in signaling networks of colorectal cancer cells

“…On the contrary, the LoF of AKT prevails on the GoF of PI3K as their combination increases p53 concentration. This could be due to the relationship between PI3K and AKT since PI3K activation is upstream to the AKT signal (Naderali et al, 2019) . Therefore, AKT reduction plays a predominant role on p53 levels regardless of PI3K activation.…”