PTEN/PI3K/Akt pathway alters sensitivity of T-cell acute lymphoblastic leukemia to l-asparaginase

Abstract

Childhood T-cell acute lymphoblastic leukemia (T-ALL) still remains a therapeutic challenge due to relapses which are resistant to further treatment. l-asparaginase (ASNase) is a key therapy component in pediatric T-ALL and lower sensitivity of leukemia cells to this drug negatively influences overall treatment efficacy and outcome. PTEN protein deletion and/or activation of the PI3K/Akt signaling pathway leading to altered cell growth and metabolism are emerging as a common feature in T-ALL. We herein investigated the relationship amongst PTEN deletion, ASNase sensitivity and glucose metabolism in T-ALL cells. First, we found significant differences in the sensitivity to ASNase amongst T-ALL cell lines. While cell lines more sensitive to ASNase were PTEN wild type (WT) and had no detectable level of phosphorylated Akt (P-Akt), cell lines less sensitive to ASNase were PTEN-null with high P-Akt levels. Pharmacological inhibition of Akt in the PTEN-null cells rendered them more sensitive to ASNase and lowered their glycolytic function which then resembled PTEN WT cells. In primary T-ALL cells, although P-Akt level was not dependent exclusively on PTEN expression, their sensitivity to ASNase could also be increased by pharmacological inhibition of Akt. In summary, we highlight a promising therapeutic option for T-ALL patients with aberrant PTEN/PI3K/Akt signaling.

Vasoactive intestinal peptide exerts therapeutic action by regulating PTEN in a model of Sjögren's disease

“…31 Interestingly, accumulating data have demonstrated that activation of the PI3K/AKT pathway is involved in modulating the T cell subsets, including the balance of Treg/Th17 cells. 32,33 The function and differentiation of T cells are precisely, thus avoiding the impairment of normal organizations. In abnormal conditions, T-cell activation can induce inflammation and local damage.…”

Possible mechanism of metabolic and drug resistance with L-asparaginase therapy in childhood leukaemia

“…PTEN is a major negative regulator of the PI3K/Akt/mTOR signalling pathway. Deletion of PTEN can occur in 20% of children with T-ALL and plays an important role in the development and prognosis of T-ALL in children (51)(52)(53). Hlozkova et al proposed that the metabolic pattern of leukaemic cells is associated with L-ASNase resistance after investigating the effect of L-ASNase treatment on the extensive metabolic reprogramming of leukaemic cells.…”

“…PTEN is a major negative regulator of the PI3K/Akt/mTOR signalling pathway. Deletion of PTEN can occur in 20% of children with T-ALL and plays an important role in the development and prognosis of T-ALL in children ( 51 – 53 ). Hlozkova et al.…”

“…found that, compared to PTEN wild-type cells, PTEN-deficient T-ALL cells have a higher glycolytic function and overactivated Akt, and these changes made T-ALL cells resistant to L-ASNase. Meanwhile, the resistance of PTEN-deficient cells to L-ASNase could be improved by inhibiting Akt signalling ( 53 ). These results suggest that Akt inhibitors may contribute to the treatment of T-ALL patients with PTEN mutations, but further experiments are still needed for verification.…”

Suppression of malignant melanoma by knocking down growth differentiation factor-15 via inhibiting PTEN/PI3K/AKT signaling pathway

“…For example, Berberine regulated the Notch1/PTEN/PI3K/AKT/mTOR pathway and acted synergistically with 17-AAG and SAHA in SW480 colon cancer cells 10 . PTEN/PI3K/Akt pathway alters sensitivity of T-cell acute lymphoblastic leukemia to L-asparaginase 13 . Therefore, targeting this pathway may be a promising strategy for the treatment of cancer.…”