Role of Ubiquitination in PTEN Cellular Homeostasis and Its Implications in GB Drug Resistance

Abstract

Glioblastoma (GB) is the most common and aggressive brain malignancy, characterized by heterogeneity and drug resistance. PTEN, a crucial tumor suppressor, exhibits phosphatase-dependent (PI3K-AKT-mTOR pathway)/independent (nucleus stability) activities to maintain the homeostatic regulation of numerous physiological processes. Premature and absolute loss of PTEN activity usually tends to cellular senescence. However, monoallelic loss of PTEN is frequently observed at tumor inception, and absolute loss of PTEN activity also occurs at the late stage of gliomagenesis. Consequently, aberrant PTEN homeostasis, mainly regulated at the post-translational level, renders cells susceptible to tumorigenesis and drug resistance. Ubiquitination-mediated degradation or deregulated intracellular localization of PTEN hijacks cell growth rheostat control for neoplastic remodeling. Functional inactivation of PTEN mediated by the overexpression of ubiquitin ligases (E3s) renders GB cells adaptive to PTEN loss, which confers resistance to EGFR tyrosine kinase inhibitors and immunotherapies. In this review, we discuss how glioma cells develop oncogenic addiction to the E3s-PTEN axis, promoting their growth and proliferation. Antitumor strategies involving PTEN-targeting E3 ligase inhibitors can restore the tumor-suppressive environment. E3 inhibitors collectively reactivate PTEN and may represent next-generation treatment against deadly malignancies such as GB.

Recent advances in PTEN signalling axes in cancer

“…In sum, these studies add to an increasing body of data demonstrating the diverse consequences of conjugation of monomeric ubiquitin or ubiquitin chains to PTEN including stability, cellular localisation, protein interactions, and catalytic activity 54 , 55 . The study by Lee et al also exemplifies that agents with modulating effects on ubiquitin ligases and/or deubiquitinases may also be relevant targets for the development of therapies aiming to indirectly enhance PTEN expression 48 .…”

Loss of PR55α promotes proliferation and metastasis by activating MAPK/AKT signaling in hepatocellular carcinoma

“…Complete activation of AKT required phosphorylation at Ser473 by mTORC2 and at Thr308 by PDK1 [ 27 , 28 ]. AKT is activated by various kinases, such as PKA, ACK1 and TNK2, and is inhibited by a variety of phosphatases, such as PP2A, PTEN, PHLPPs and INPP4B [ 6 , 29 ]. A previous study confirmed that PR55α can directly bind and induce preferential dephosphorylation of phospho-Thr-308 instead of phospho-Ser-473, as evidenced by in vitro assays on dephosphorylation using both NIH3T3 and FL5.12 cells [ 30 ].…”

Loss of PR55α promotes proliferation and metastasis by activating MAPK/AKT signaling in hepatocellular carcinoma

“…Complete activation of AKT required phosphorylation at Ser473 by mTORC2 and at Thr308 by PDK1 27,28 . AKT is activated by various kinases, such as PKA, ACK1 and TNK2, and is inhibited by a variety of phosphatases, such as PP2A, PTEN, PHLPPs and INPP4B 6,29 . A previous study con rmed that PR55α can directly bind and induce preferential dephosphorylation of phospho-Thr-308 instead of phospho-Ser-473, as evidenced by assays on in vitro dephosphorylation using both NIH3T3 and FL5.12 cells 30 .…”