PTEN

Overview

PTEN (Phosphatase and Tensin Homolog) is a dual-specificity tumor suppressor protein encoded by the PTEN gene on chromosome 10q23. It functions primarily as a lipid phosphatase that dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate (PIP3), thereby acting as the principal negative regulator of the PI3K/AKT/mTOR signaling pathway — one of the most frequently dysregulated axes in human cancer. By opposing the activity of PI3-kinase, PTEN limits Akt1 activation and downstream pro-survival and proliferative signaling through the mechanistic target of rapamycin kinase (mTOR). Beyond its cytoplasmic phosphatase function, PTEN is also capable of nuclear translocation, where it participates in DNA damage response, chromosomal stability, and transcriptional regulation. Loss of PTEN function — through deletion, mutation, promoter silencing, or post-translational inhibition — is among the most common molecular alterations in human malignancy, occurring across many tumor types, and is frequently associated with poor prognosis, therapy resistance, and aggressive disease biology.

PTEN's tumor suppressive role extends beyond oncology. It is a critical regulator of neuronal survival, synaptic plasticity, and metabolic homeostasis, and its dysfunction has been implicated in neurodegenerative conditions, cognitive impairment, and metabolic syndromes. Because PTEN sits at the convergence of growth factor signaling, apoptosis, autophagy pathways, and immune regulation, it has emerged as a high-priority node in both basic and translational biomedical research.

Focus of Latest Publications

Recent publications have continued to position PTEN as a central tumor suppressor and signaling node across cancer and noncancer models. In hepatocellular carcinoma, PTEN was linked to oncogenic regulation by CNOT9, where CNOT9 knockdown activated PTEN, inhibited AKT signaling, and reduced proliferation while increasing apoptosis and G2-phase arrest. A separate hepatocellular carcinoma study identified pentagalloylglucose (PGG) as an orally available small-molecule inhibitor that suppresses AP5Z1-mediated ubiquitination and degradation of PTEN, thereby blocking downstream PI3K/AKT/mTOR signaling and reducing tumor growth in vitro and in vivo. PTEN was also implicated in a breast cancer study of androgen receptor agonism, where EP0062 showed antitumor activity in estrogen receptor-positive metastatic breast cancer models, including tumors with PTEN mutations.

Several studies focused on PTEN in the context of therapy resistance and pathway modulation. In pancreatic ductal adenocarcinoma, Aurora kinase A was shown to promote radioresistance by interacting with GSK3β and driving inhibitory phosphorylation of PTEN at T366, which impaired PTEN phosphatase activity and sustained PI3K/AKT/mTOR signaling; this phenotype was reversed by GSK3β knockdown or a PTEN-T366A mutant. In prostate cancer, SHLD2 loss was reported to frequently co-occur with PTEN loss in a subset of tumors, although the enhanced radiosensitization to polymerase theta inhibition plus radiotherapy was independent of PTEN status. A review of metastatic castration-resistant prostate cancer also highlighted protein kinase B inhibitors as a strategy for the PTEN-loss subset.

PTEN was additionally studied in regenerative and delivery-based approaches. In spinal cord injury models, platelet-rich plasma-primed bone marrow mesenchymal stem cell-derived exosomes delivered miR-29a-3p, which targeted PTEN and modulated the PTEN/PI3K/Akt/mTOR axis to inhibit neuronal apoptosis and autophagy while promoting nerve regeneration. In glioblastoma, mannose-cholesterol lipid nanoparticles carrying PTEN mRNA crossed the blood-brain barrier, accumulated preferentially in orthotopic tumors, restored tumor suppression, reduced tumor burden, and extended survival in mice. Another nanoparticle-based study used curcumin-loaded CRISPR-supported polymeric nanoparticles to silence Kras-G12D while increasing PTEN expression in metastatic pulmonary cancer cells.

PTEN also appeared in studies of apoptosis, metastasis, and neurotoxicity. In triple-negative breast cancer cells, betulinic acid and doxorubicin were associated with miR-21 downregulation and increased PTEN expression, alongside apoptosis and growth arrest. In another breast cancer study, Otostegia fruticosa treatment altered PTEN expression together with p-Akt, caspase-related markers, and metastasis-associated proteins, consistent with reduced invasion and migration. Outside oncology, ERα agonism was investigated in aged female mice exposed to sevoflurane, with PTEN nuclear translocation proposed as a mediator of hippocampal synaptic and cognitive deficits.

Key Publications

• NEWJul CNOT9 affects hepatocellular carcinoma proliferation and cell cycle through the PTEN/AKT/p53 signaling pathway. (Human cell, 2026, PMID 42384246): "CNOT9 knockdown activates PTEN to inhibit the AKT pathway and suppresses the expression of cell cycle-related proteins p53, p21, CCNE1 and CDK2."
• NEWJun Antitumor effect of the AP5Z1 small-molecule inhibitor PGG in hepatocellular carcinoma. (Medical oncology (Northwood, London, England), 2026, PMID 42347921): "PGG acts by inhibiting AP5Z1-mediated ubiquitination and degradation of the tumor suppressor PTEN, thereby blocking the downstream PI3K/AKT/mTOR signaling pathway."
• NEWJun Exploiting androgen receptor agonism as a treatment strategy in estrogen receptor-positive metastatic breast cancer. (NPJ breast cancer, 2026, PMID 42310300): "EP0062 displayed comparable antitumor efficacy to selective ER degraders (SERDs), including in PDXs with ESR1, PIK3CA, or PTEN mutations."
• NEWJun Single-ligand dual-targeting lipid nanoparticles for therapeutic mRNA delivery to glioblastoma across the blood-brain barrier. (Journal of controlled release : official journal of the Controlled Release Society, 2026, PMID 42297114): "In orthotopic glioblastoma models, phosphatase and tensin homolog (PTEN) mRNA-loaded MC_LNPs exhibit preferential tumor accumulation, restoring tumor suppression, reducing tumor burden 6-fold, and extending median survival from 33 to 49 days."
• NEWJun SHLD2 loss is a synthetic vulnerability to Polθ inhibition combined with radiotherapy. (Science advances, 2026, PMID 42284420): "We found that SHLD2 is deleted in a subset of human prostate cancers, frequently alongside PTEN loss, an adverse prognostic factor."
• Jun Targeting XIAP-coordinated PKC signaling resensitizes PD-1-refractory tumors for rechallenge. (Proceedings of the National Academy of Sciences of the United States of America, 2026, PMID 42234523): "Mechanistically, PKC blockade destabilizes XIAP, relieving caspase inhibition, stabilizing PTEN, and suppressing Wnt/β-Catenin-ATF3 signaling to drive CCL4 expression."
• Jun ERα Agonist Protects Aged Female Mice From Sevoflurane Neurotoxicity via PTEN Nuclear Translocation. (CNS neuroscience & therapeutics, 2026, PMID 42212628): "This study aimed to investigate whether PTEN nuclear translocation mediates sevoflurane-induced hippocampal synaptic and cognitive deficits in aged female mice, and whether activation of ERα can mitigate these effects."
• Jan Ethanolic extract of Otostegia fruticosa induces ROS-dependent apoptosis and reduces migration of MDA-MB-231 cells in vitro. (PloS one, 2026, PMID 42189838): "Altogether, this study demonstrates that Otostegia fruticosa induces apoptosis and inhibits metastasis in MDA-MB-231 cells by regulating caspase-3, 8, and 9, Bcl2, Bax, and Bid."
• May Platelet-rich plasma-primed bone marrow mesenchymal stem cell-derived exosomes inhibit neuronal apoptosis and autophagy, and promote nerve regeneration via the miR-29a-3p/PTEN/PI3K/Akt/mTOR axis after spinal cord injury. (Journal of molecular histology, 2026, PMID 42165939): "Bioinformatic analysis and luciferase assays indicated that PTEN may be a downstream target gene of miR-29a-3p."
• May Betulinic acid is associated with miR-21 modulation, apoptosis and redox changes in breast cancer cells: an in vitro and in silico study. (Scientific reports, 2026, PMID 42143107): "Besides, the potential effect of BA and DOX treatment on downstream effect of miR-21 on HIF1A, PDCD4, PTEN and SMAD7 expression levels."