Journal Article

Tumour suppressor PTEN activity is differentially inducible by myo‐inositol phosphates

Grzymajlo, Krzysztof, El Hafny‐Rahbi, Bouchra, Kieda, Claudine

2023

Overview

Tumour evolution and efficacy of treatments are controlled by the microenvironment, the composition of which is primarily dependent on the angiogenic reaction to hypoxic stress. Tumour angiogenesis normalization is a challenge for adjuvant therapy strategies to chemo‐, radio‐ and immunotherapeutics. Myo‐inositol trispyrophosphate (ITPP) appears to provide the means to alleviate hypoxia in the tumour site by a double molecular mechanism. First, it modifies the properties of red blood cells (RBC) to release oxygen (O2) in the hypoxic sites more easily, leading to a rapid and stable increase in the partial pressure of oxygen (pO2). And second, it activates the endothelial phosphatase and tensin homologue deleted on Chromosome 10 (PTEN). The hypothesis that stable normalization of the vascular system is due to the PTEN, a tumour suppressor and phosphatase which controls the proper angiogenic reaction was ascertained. Here, by direct biochemical measurements of PTEN competitive activity in relation to PIP2 production, we show that the kinetics are complex in terms of the activation/inhibition effects of ITPP with an inverted consequence towards the kinase PI3K. The use of the surface plasmon resonance (SPR) technique allowed us to demonstrate that PTEN binds inositol derivatives differently but weakly. This method permitted us to reveal that PTEN is highly sensitive to the local concentration conditions, especially that ITPP increases the PTEN activity towards PIP3, and importantly, that PTEN affinity for ITPP is considerably increased by the presence of PIP3, as occurs in vivo. Our approach demonstrates the validity of using ITPP to activate PTEN for stable vessel normalization strategies.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: 1-Phosphatidylinositol 3-kinase / Angiogenesis / Blood / Cancer / Chromosome 10 / Erythrocytes / Genotype & phenotype / Hemoglobin / Humans / Hypoxia / Hypoxia - metabolism / Inositol / Inositol Phosphates - pharmacology / ITPP / Kinases / Microenvironments / MicroRNAs / Microscopy / Original / Oxygen - metabolism / Phosphatase / Phosphatidylinositol 3,4,5-triphosphate / Phosphatidylinositol 4,5-diphosphate / Phosphoric Monoester Hydrolases / PTEN / PTEN Phosphohydrolase / PTEN protein / Surface plasmon resonance / Tumor suppressor genes / Tumors / Vascular endothelial growth factor / Vascular system