GSTT1 promotes stemness and FGFR inhibitor sensitivity in pancreatic cancer through regulation of CD133 (PROM1).

NKD1 promotes the progression and 5-FU resistance of colorectal cancer via the Wnt/β-catenin signaling.

5-Fluorouracil (5-FU) resistance continues to pose a considerable barrier in the postoperative management of advanced colorectal cancer (CRC). This study identified Naked cuticle homolog 1 (NKD1) as a key factor associated with 5-FU resistance in CRC based on sequencing data from the GEO and TCGA databases. Elevated NKD1 expression correlated with adverse clinicopathological features and poor patient survival. Functional assays revealed that NKD1 overexpression elevated the IC50 of 5-FU, promoted tumor cell proliferation, and attenuated apoptosis in both drug-treated and untreated settings. Additionally, NKD1 promoted CRC cell migration and invasion, regulated tumor stem cell markers. Mechanistically, NKD1 stabilizes DVL protein, regulates APC and FZD7, and fosters nuclear accumulation of β-catenin, initiating transcriptional programs downstream of Wnt signaling. Silencing NKD1 synergized with 5-FU to improve therapeutic efficacy in patient-derived organoid and xenograft models. These results establish NKD1 as a key regulator of CRC malignancy and chemoresistance via Wnt/β-catenin pathway activation, supporting its potential as a dual biomarker and therapeutic target in combination regimens.

p140Cap enhances breast cancer chemosensitivity by limiting an ABCC1-enriched stem-like compartment via β-Catenin inhibition

Targeting PSMB2 suppresses glioblastoma progression and sensitizes tumors to temozolomide by modulating PTEN/PI3K/AKT pathway.

Glioblastoma multiforme (GBM), a highly aggressive primary brain malignancy, is characterized by its accelerated development, refractoriness to therapy, and dismal prognosis. The proteasome subunit β2 (PSMB2), a catalytic unit of the 20S proteasome, has been linked to tumorigenesis across multiple malignancies; however, its signaling and therapeutic relevance in GBM remains incompletely defined. U87 and U251 GBM cells were engineered to overexpress (OE-PSMB2) or silence (Sh-PSMB2) PSMB2. We assessed the function of PSMB2 in GBM cell proliferation, migration, and related phenotypes, and further examined its association with the PTEN/PI3K/AKT signaling axis at both transcriptomic and protein levels. A xenograft model was conducted in the intracranial setting where the therapeutic efficacy of PSMB2 silencing, when used together with temozolomide (TMZ), was assessed. PSMB2 overexpression stimulated GBM cell proliferation, migration, and invasion, and PSMB2 silencing inhibited these phenotypes and promoted apoptosis. RNA-seq showed that PI3K/AKT pathway was enriched in Sh-PSMB2 cells. Protein-level analysis showed that PSMB2 expression was inversely associated with PTEN abundance and was accompanied by altered PI3K/AKT pathway activity. PSMB2 silencing decreased tumor burden and increased survival in vivo, and the combination of PSMB2 silencing and TMZ produced the greatest therapeutic effect. PSMB2 may function as a tumor-promoting regulator in GBM and is associated with PTEN/PI3K/AKT pathway modulation. Targeting PSMB2 suppressed tumor progression and enhanced the therapeutic response to TMZ in vivo, suggesting that PSMB2 may represent a potential therapeutic target for GBM.

Pan-cancer profiling of CDH2 and a GSK3β-sensitive anti-proliferative effect in K562 chronic myeloid leukemia cells.

Chronic myeloid leukemia (CML) is driven by uncontrolled myeloid proliferation, yet underlying molecular mechanisms remain incompletely understood. This study investigated the pan-cancer expression profile of N-cadherin (CDH2) and its potential role in suppressing proliferation in K562 CML cells, with an exploratory focus on the GSK3β/β-catenin axis. We combined in silico analyses (TCGA/GEO datasets) with functional assays in K562 cells. CDH2 expression was assessed across 31 cancer types. In K562 cells, we evaluated the effects of CDH2 overexpression on proliferation, cell cycle, apoptosis, and several proteins within the β-catenin/GSK3β network. CDH2 was significantly upregulated in 18 malignancies and downregulated in 10. It was associated with adverse overall survival in five solid tumors but favorable in KIRC. In acute myeloid leukemia (AML), higher CDH2 expression correlated with poor-prognosis cytogenetic risk (P = 0.008). CDH2 expression also correlated with macrophage/NK cell infiltration in some solid tumors. In K562 cells, CDH2 overexpression suppressed proliferation, induced cell cycle arrest and early apoptosis. This was accompanied by increased total β-catenin protein but a reduced nuclear-to-cytoplasmic β-catenin ratio, without consistent changes in canonical Wnt target gene expression. Notably, the GSK3 inhibitor CHIR-99,021 reversed the anti-proliferative effect of CDH2, whereas the β-catenin degrader MSAB did not rescue it. CDH2 exhibits context-dependent expression across malignancies. In K562 CML cells, CDH2 overexpression suppresses proliferation through a GSK3β-sensitive mechanism. However, the precise molecular mechanism remains unresolved. Our findings suggest that targeting GSK3β may represent a therapeutic vulnerability in this model.

Mechanistic evaluation of NSC 57774 as a SHP2 inhibitor in gastric cancer: Multi-pathway signaling modulation in vitro

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, driven by late-stage diagnosis, metastatic progression, and therapeutic resistance. Src homology region 2 domain-containing phosphatase 2 (SHP2) has emerged as a critical regulator of oncogenic signaling in gastric tumorigenesis, yet its therapeutic targeting remains underexplored. In this study, we evaluated the anti-cancer efficacy of NSC 57774, a novel SHP2 inhibitor, using integrated bioinformatics and functional assays in AGS gastric cancer cells. Analysis of The Cancer Genome Atlas (TCGA) and UALCAN datasets revealed marked upregulation of SHP2 and multiple receptor tyrosine kinases in gastric cancer tissues. NSC 57774 potently inhibited cell proliferation and migration, demonstrating selective cytotoxicity towards cancer cells over non-cancerous fibroblasts. Mechanistically, NSC 57774 disrupted key oncogenic pathways including MAPK/ERK, AKT and STAT3 in a concentration- and time-dependent manner, with higher doses achieving more sustained pathway suppression. NSC 57774 suppressed NF-κB inflammatory signaling at early timepoints and induced cleaved caspase-3 across all treatment groups at 72 hours, indicative of pro-apoptotic activity. A paradoxical late-phase increase in phospho-p38 was observed at 72 hours, consistent with a compensatory pro-apoptotic stress response. Comparative analysis revealed that NSC 57774 outperformed the commercial SHP2 inhibitor NSC 87877 and doxorubicin in reducing viability and migration of gastric cancer cells. Collectively, these findings position NSC 57774 as a promising candidate for targeted gastric cancer therapy, capable of disrupting multiple signaling pathways involved in tumor progression, metastasis, and inflammation, warranting further preclinical and clinical investigation.

IGFBP5 suppresses colorectal cancer stemness and carcinogenesis via binding to GPR182 and inhibiting PKCα/AKT/P70S6K axis.

Excessive proliferation of crypt stem cells represents a crucial hallmark in colorectal tumorigenesis. G protein-coupled receptor 182 (GPR182), a recently partially "deorphanized" G protein-coupled receptor (GPCR), has emerged as a pivotal modulator in gastrointestinal tumors. However, its roles and underlying mechanism in colorectal tumors remain unclear, primarily due to the absence of identified endogenous ligands. In this study, we identified Insulin like growth factor binding protein 5 (IGFBP5) as a novel endogenous ligand for GPR182. GPR182 mRNA and protein expression levels were significantly up-regulated in cancer stem cells of colorectal tissues or cell lines. Functional assays revealed that IGFBP5 inhibited growth of intestinal crypt organoids and cancer stem cell spheres. In APCMin/+ mice, IGFBP5 administration attenuated the tumor development while co-administration of GPR182 knockdown adeno-associated virus (AAV) abrogated this phenotype. Consistently, systemic IGFBP5 knockout markedly accelerated tumorigenesis and shortened survival time in APCMin/+ mice. Mechanistic investigations demonstrated that IGFBP5's engagement with GPR182 induced inhibition of AKT/P70S6K pathway via Protein kinase C alpha (PKCα) dephosphorylation. Together, these findings elucidate the suppressive role of IGFBP5 in colorectal cancer (CRC) stem cells via GPR182/PKCα/AKT/P70S6K axis, highlighting IGFBP5 implementation a promising strategy for CRC.