SEARCH · PubMed Health

Results for “PI3K/mTOR pathway”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

4 recordsLinked to original sources

PubMed2026

A rare germline TXNIP missense mutation may contribute to the genesis of familial ovarian mature teratoma in human.

Ovarian mature teratoma (OT) is a common ovarian germ cell tumor, and its early onset, multifocality, recurrence and familial aggregation suggest that genetic susceptibility contributes to a subset of cases. Whole-exome sequencing was used to identify candidate susceptibility variants in a family with recurrent and multifocal OT. A rare heterozygous germline TXNIP variant, NM_006472.6:c.1049C > T (p.Pro350Leu), was identified and confirmed by Sanger sequencing. p.Pro350Leu TXNIP showed lower steady-state abundance, faster cycloheximide-chase decay, and greater K48-linked polyubiquitination than wild-type TXNIP. Familial OT specimens also showed weaker TXNIP staining and stronger GLUT1 staining than sporadic OT specimens. TXNIP depletion increased plasma-membrane GLUT1, glucose uptake, lactate production and hyperactivated the PI3K/mTOR pathway, and familial tissues reproduced this PI3K/mTOR-dominant state. To our knowledge, this is the first genomic and functional investigation of a germline susceptibility mechanism for human familial ovarian mature teratoma. These findings establish TXNIP as the first functional candidate susceptibility gene for this phenotype and connect inherited susceptibility to ubiquitin-dependent protein turnover, GLUT1-driven metabolic reprogramming, and PI3K/mTOR-dominant follicular signaling.

Missense mutation↗

PubMed2026

Overexpression of TCF7L2 promotes the viability and migration of MHCC-97H human hepatocellular carcinoma cells by upregulating MT-ND4L.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive cancer with high metabolic adaptability. TCF7L2, a transcription factor implicated in type 2 diabetes and cancer, is overexpressed in HCC. However, its specific role in HCC metabolic reprogramming is not well defined. We aimed to elucidate the previously unrecognized molecular mechanisms through which TCF7L2 impacts HCC progression. METHODS: To investigate the function of TCF7L2, a stable MHCC-97H cell line with TCF7L2 overexpression was established via lentiviral transduction. Cell viability and migration were assessed by Cell Counting Kit-8 (CCK-8) and Transwell assays. Transcriptomic profiling [RNA sequencing (RNA-seq)] was performed to identify differentially expressed genes (DEGs). Functional enrichment analysis [Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA)] and bioinformatics promoter analysis (the JASPAR CORE database) were conducted. Clinical correlations, survival analysis, and tumor microenvironment (TME) interrogation were performed using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and single-cell datasets [Human Protein Atlas (HPA), CellChat]. Drug sensitivity was predicted via the Genomics of Drug Sensitivity in Cancer (GDSC) database. RESULTS: TCF7L2 overexpression significantly promoted HCC cell proliferation and migration. Transcriptomic analysis revealed that TCF7L2 drives a profound metabolic shift, with key enrichments in lipid homeostasis, fatty acid β-oxidation, and the PI3K/Akt pathway. Mechanistically, TCF7L2 directly binds to the promoter of CPT1A, the rate-limiting enzyme of fatty acid oxidation, and indirectly upregulates the mitochondrial gene MT-ND4Lvia a strong positive correlation with the mitochondrial transcription factor TFAM. In clinical cohorts, TCF7L2 was overexpressed in HCC and its expression correlated positively with MT-ND4L, MKI67, and SNAI1, and served as a predictor of poor overall survival (OS). Furthermore, TCF7L2-high tumors were enriched in hepatic progenitor cell (HPC)-like niches, mediated by enhanced ANGPTL4 signaling. High TCF7L2 expression predicted increased sensitivity to PI3K/mTOR pathway inhibitors. CONCLUSIONS: TCF7L2 acts as a master metabolic regulator in HCC, coordinating lipid catabolism and mitochondrial biogenesis to drive aggressive tumor behavior. It further remodels the TME towards an HPC-like state and predicts sensitivity to metabolic-targeted therapies. These findings identify TCF7L2 as a key prognostic biomarker and a promising therapeutic target.

MHCC-97H hepatocellular carcinoma cells (MHCC-97H ↗

PubMed2024

Just a spoonful of metformin helps the medicine go down.

Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor with a need for novel therapies. So far, monotherapies have failed to prolong survival for these patients, and combinatorial strategies have often shown severe, dose-limiting toxicities. In this issue of the JCI, Duchatel, Jackson, and colleagues address this challenge by introducing a drug combination that mitigates side effects and overcomes resistance. After identifying the PI3K/mTOR pathway as a therapeutic vulnerability, they treated DIPG-bearing mice with paxalisib and saw responses but also observed hyperglycemia as a severe side effect. Combining paxalisib with metformin mitigated this toxicity, but also upregulated protein kinase C (PKC) signaling. To tackle this mechanism of resistance, the authors added the PKC inhibitor enzastaurin to their drug combination and showed that this triple therapy led to improved survival. This approach paves the way for improved outcomes for patients with DIPG and other brain tumors.

Humans↗

PubMed2026

PIK3CA in Cancer: Structure, Biology, Alterations, and Actionability.

PIK3CA, which encodes the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), is one of the most frequently altered oncogenes in human cancer and a major driver of tumor initiation, progression, metastasis, and therapeutic resistance. Over the past two decades, advances in structural biology, cancer genomics, and translational research have substantially expanded our understanding of PIK3CA function and established the PI3K pathway as a clinically actionable therapeutic target. This review provides an overview of the structural organization and physiological functions of the PI3Kα complex, the molecular mechanisms underlying oncogenic activation, and the diverse spectrum of PIK3CA alterations across human malignancies. We also summarize the current landscape of PI3K-targeted therapies, highlighting both approved agents and emerging therapeutic strategies. Clinical evidence supports the rational integration of PI3K inhibitors with endocrine therapy, CDK4/6 inhibitors, MAPK pathway inhibitors, dual PI3K/mTOR inhibition, and immune checkpoint blockade. In addition, accumulating evidence indicates that PIK3CA plays a pivotal role in shaping the tumor immune microenvironment, providing a biological rationale for combining PI3K inhibition with immunotherapy. Finally, we discuss future directions in precision oncology, emphasizing integrated molecular profiling, liquid biopsy, single-cell and spatial technologies, functional genomics, and evolutionary approaches as complementary strategies to refine patient selection, overcome therapeutic resistance, and optimize clinical outcomes.

PI3K signaling↗