Targeting the Osteopontin-regulated PI3K/AKT signaling pathway: A molecular approach to overcome drug resistance and metastasis in gastrointestinal tumors

Abstract

Osteopontin (OPN), a key extracellular matrix protein, promotes gastrointestinal tumor progression by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. OPN enhances tumor proliferation and survival through mechanistic target of rapamycin and B-cell lymphoma 2 upregulation (e.g., via denticleless E3 ubiquitin protein ligase homolog in hepatocellular carcinoma) and drives metastasis via PI3K/AKT-mediated epithelial-mesenchymal transition and androgen receptor (AR) activation (e.g., via the OPN-RAN-AR axis in pancreatic cancer). Additionally, OPN induces chemoresistance by activating anti-apoptotic proteins (e.g., XIAP via CXCR3/PI3K/AKT in colorectal cancer) and remodels the tumor microenvironment through VEGF-dependent angiogenesis and cluster of differentiation 44-PI3K/AKT-mediated immune evasion. Its interaction with TLR4, WNT, and other pathways amplifies oncogenic effects. Therapies targeting the OPN-PI3K/AKT axis (e.g., PI3K inhibitors like LY294002) or combination treatments (e.g., with EGFR-TKIs) show promise for reversing drug resistance. Future research should focus on OPN isoform specificity, clinical translation, and interactions with autophagy and long non-coding RNAs to refine precision therapies. This review summarizes recent advances in understanding the molecular mechanisms, therapeutic targets, and clinical challenges of the OPN-PI3K/AKT axis in gastrointestinal tumors, providing a foundation for overcoming resistance and developing precision therapies.

Keywords: Osteopontin; Gastrointestinal cancers; Chemoresistance; Targeted therapy; Tumor microenvironment remodeling

Core Tip: Osteopontin (OPN) drives gastrointestinal tumor progression by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, promoting proliferation, metastasis, chemoresistance, and immune evasion. Key mechanisms involve upregulating anti-apoptotic proteins (e.g., B-cell lymphoma 2), inducing epithelial-mesenchymal transition via Snail/Twist, and remodeling the tumor microenvironment through VEGF-driven angiogenesis and cluster of differentiation 44-mediated immune suppression. Targeting this axis with PI3K/AKT inhibitors (e.g., Alpelisib) or OPN-neutralizing antibodies may reverse drug resistance and suppress metastasis. Challenges include pathway redundancy and the need for biomarker-guided precision strategies. Future research should focus on OPN isoform specificity, combination therapies (e.g., with immune checkpoint inhibitors), and multi-omics approaches to optimize outcomes in refractory cancers.