AIMS:To explore the roles of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and poly(ADP-ribose) polymerase 1 (PARP1) in both the DNA damage repair (DDR) pathway and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway mediated immune response, and to analyze the therapeutic potential of their inhibitors. METHODS:This is a review article synthesizing recent findings on the functions of DNA-PKcs and PARP1 in DDR, their context-dependent effects on the cGAS-STING pathway and the therapeutic mechanisms of their inhibitors. RESULTS:DNA-PKcs and PARP1 are key components of two major DDR mechanisms. Beyond their canonical repair functions, both factors significantly regulate the cGAS-STING pathway, a central mediator linking cytoplasmic DNA and the type I interferon response. CONCLUSION:DNA-PKcs and PARP1 connect genome maintenance with innate immune signaling through context-dependent mechanisms. Targeting these proteins represents a promising strategy for modulating cGAS-STING signaling and improving disease treatment.
BACKGROUND:Cellular plasticity and epithelial-mesenchymal transition (EMT) promote the initiation and progression of non-small cell lung cancer (NSCLC). Thioredoxin reductase 1 (TXNRD1), a key redox enzyme, has been linked to malignancy, but its mechanism in NSCLC remains unclear. We examined whether TXNRD1 regulates TGF-β1 autocrine signaling to drive EMT and stemness. MATERIALS:Stage-progression gene profiles were analyzed in the TCGA and GEO databases with an emphasis on redox gene families. TXNRD1 was manipulated by overexpression or knockdown in A549, H226, and H1299 cells, followed by migration/invasion, spheroid assays, ELISA for cytokines, and RT-qPCR/Western blot for EMT markers. RNA-seq with pathway enrichment analyses was used to identify downstream programs. An orthotopic lung cancer mouse model was established using TXNRD1-WT cells, TXNRD1-deficient cells, and TXNRD1-deficient cells treated with TRi-1. Tumor progression was monitored by bioluminescence imaging at 6 and 12 weeks after transplantation. RESULTS:TXNRD1 expression was ~2-fold higher in advanced-stage NSCLC and was validated in tumor tissues. CRISPR/Cas9 or siRNA knockdown reduced EMT-associated genes and decreased TGF-β1 production in A549 and H226 cells. TXNRD1 overexpression increased EMT and stemness markers and produced larger, more compact spheres with higher sphere numbers in H1299 cells. RNA-seq indicated the TXNRD1 pathway activates the TGF-β1 pathway to promote EMT, motility, and stemness via an autocrine loop; knockdown or TXNRD1 inhibition suppressed metastatic tumor growth in vivo. CONCLUSIONS:Our study identifies TXNRD1 as a crucial regulator of cellular plasticity and metastasis in NSCLC via the TGF-β1 pathway, suggesting that targeting TXNRD1 may reduce metastatic potential and improve patient survival.
The recent study by Liu et al. provided compelling preclinical evidence that lenvatinib enhances the efficacy of combined radiotherapy and PD-L1 blockade by modulating both angiogenesis and antitumor immunity in lung adenocarcinoma. In this correspondence, I discuss the translational implications of these findings and highlight several challenges that should be addressed before clinical implementation. These include the molecular heterogeneity of lung adenocarcinoma, interpatient variability in the temporal dynamics of vascular normalization and immune activation, and the limitations of relying solely on PD-L1 expression for patient selection. I further emphasize the need for biomarker-driven and adaptive clinical trial designs incorporating functional imaging, circulating biomarkers, and immune monitoring to optimize treatment timing and identify patients most likely to benefit from this therapeutic strategy. These considerations may facilitate the successful translation of promising preclinical observations into precision radioimmunotherapy for lung adenocarcinoma.
Platelets, traditionally recognized for their role in hemostasis, are now understood to actively contribute to tumor progression, angiogenesis, and metastasis. Through dynamic bidirectional interactions with cancer cells, platelets undergo measurable alterations in count, mean platelet volume, and molecular cargo, including proteins and mRNAs, supporting their potential utility as liquid biopsy biomarkers for early cancer detection. Within the tumor microenvironment, platelets contribute to immune evasion, support tumor cell intravasation and extravasation, enhance the survival of circulating tumor cells, and promote neovascularization. In addition, they can physically shield malignant cells from immune surveillance, thereby increasing metastatic potential. Although context-specific anti-tumor effects have been reported, the predominant evidence supports a largely pro-tumorigenic and pro-metastatic role for platelets. Elucidating the molecular mechanisms underlying platelet-tumor interactions is therefore essential for improving cancer risk stratification, prognostic evaluation, and therapeutic development. This review summarizes current advances in platelet-derived biomarkers and discusses emerging therapeutic strategies targeting platelet-mediated pathways to suppress metastasis and improve clinical outcomes in cancer patients.
Colorectal cancer (CRC) remains a major global health challenge and a leading cause of cancer-related mortality worldwide. Central to its pathogenesis is the dysregulation of interconnected signal transduction networks that govern cellular proliferation, survival, differentiation, apoptosis, and immune modulation. Progressive disruption of these pathways facilitates malignant transformation of the colonic epithelium and underlies disease initiation and progression. In this review, we examine the foundational signaling mechanisms implicated in CRC, with an emphasis on the Wnt/β-catenin, GUCY2C, MAPK/ERK, p53, PI3K/AKT, and SMAD4/TGF-β pathways. We also highlight the genomic and epigenomic hallmarks of CRC to illustrate how genetic and epigenetic alterations contribute to diverse oncogenic processes. Furthermore, we discuss both conventional and emerging precision-based therapeutic strategies aimed at driving mutations in CRC tumorigenesis. By synthesizing advances in signaling biology, this review aims to provide a framework for understanding CRC complexity and to inform the development of more precise and effective therapies.
BACKGROUND:Lung cancer presents complex etiopathology involving a mix of genetic predispositions and environmental factors. The best treatment modality is surgical resection. However, it becomes ineffective in the advanced metastatic stage. Thus, cisplatin-based chemotherapy, though restricted by an intrinsic and/or acquired chemo-resistant phenotype, remains the first-line therapy for advanced non-small-cell cancer (NSCLC). METHODS:Various tools were used to verify the mRNA expression and protein levels of ABC and ALDH proteins in patient-derived non-small-cell lung cancer (NSCLC) samples (GSE102287, GSE43580) and cell lines A549 and NCI-H158 (including their respective cisplatin-resistant variants) to verify the cisplatin-sensitizing abilities of newly synthesized bis-(di-4-phenyl-benzylaminethiocarbonyl)disulfide-non-toxic ALDH and ABCC2 inhibitors. RESULTS:We identified significant molecular differences in the expression levels of ABCC1, ABCC5, ABCC3, ALDH7A1, and ALDH3A1. Additionally, a fairly significant patient subgroup (Z-score > 1.5), characterized by ABCC2 and ALDH3A1 overexpression, was identified. Importantly, in vitro, ABCC2 and ALDH3A1 accompany the acquisition of cisplatin resistance in A549 cells. Bis-(di-4-phenyl-benzylaminethiocarbonyl)disulfide reverses cisplatin resistance in a cisplatin-resistant variant of A549 cells (via ALDH and ABCC2 inhibition) but not in NCI-H158 cells. CONCLUSIONS:Molecular categorization of NSCLC cancer is essential for predicting therapy outcomes, enabling the use of bis-(di-4-phenyl-benzylaminethiocarbonyl)disulfide as a cisplatin therapy enhancer for NSCLC patients' subpopulation with significant ABCC2 and ALDH3A1 overexpression.
Background This study aimed to systematically characterize the genomic alteration landscape of phosphatidylinositol 4-kinase (PI4K) and phosphatidylinositol phosphate kinase (PIPK) family genes in solid tumors, assess the correlation of these alterations with patient clinical outcomes and the tumor immune microenvironment, and explore their potential as novel biomarkers or therapeutic targets.Methods A retrospective analysis was conducted on whole-exome sequencing data from a cohort of 2,144 Chinese patients encompassing 18 solid tumor types. Genomic and transcriptomic data from The Cancer Genome Atlas (TCGA) pan-cancer project were integrated to perform survival analysis, correlating genomic alterations, gene expression levels, and patient overall survival. Associations between these gene alterations and tumor mutational burden (TMB), microsatellite instability (MSI), and levels of tumor-infiltrating immune cells were also evaluated.Results We identified PI4K/PIPK alterations in 10.5% of 2,144 patients, with PIP4K2C amplification reaching 48%. While PI4K2B amplification and overexpression are consistently associated with poor prognosis in COAD, family-wide effects were highly heterogeneous across cancers. Alterations significantly correlated with higher TMB and MSI-H, and multi-omics analysis revealed tissue-specific immune landscapes, highlighting the family's potential for risk stratification and immunotherapy.Conclusions This study provides the first systematic delineation of the genomic alteration landscape of PI4K and PIPK families at a pan-cancer scale within a Chinese population. It identifies PI4K2B as an amplification-driven prognostic biomarker in colorectal cancer, with potential clinical value analogous to HER2. These findings illuminate the significant roles of these kinases in cancer and provide novel insights for future precision oncology strategies.
Objective: Chemokine receptors play crucial roles in tumor onset and progression, but the high redundancy between ligands and their receptors limits the possibilities to leverage them therapeutically for cancer management. To overcome this limitation, we developed chimeric chemokine peptides in which CCL2 and CCL8 were conjugated to diphtheria toxin (DT) and evaluated their antitumor activity. Methods: Cytotoxic peptides DTCCL2 and DTCCL8 were produced as recombinant proteins, and their anticancer activity was tested in vitro in cultured cells and in vivo in tumor-bearing mice. The uptake of the cytotoxic analogs was evaluated before and after therapy in tumor explants ex vivo. Results: Both analogs were cytotoxic to breast cancer cells in vitro and produced significant anticancer activity in vivo in mice bearing human breast cancer lines and hormone-negative breast cancer patient-derived xenografts (PDXs). In vitro, the peptide conjugates exhibited overlapping uptake profiles, with about 80% of the breast cancer cells being positive for both peptides and about 15%-20% of the cells being negative for either or both of the cytotoxic peptides. In tumor explants cultured ex vivo, simultaneous positivity for DTCCL2 and DTCCL8 increased to >95%, with less than 5% of the cells showing neither DTCCL8 nor DTCCL2 uptake. Treatment of breast cancer-bearing mice with DTCCL8 or DTCCL2 significantly inhibited tumor growth and prolonged survival in the PDX model. Conclusion: These results support the feasibility of cytotoxic peptide conjugates for breast cancer management and show that receptor expression profiles in vitro do not accurately forecast tumoral positivity.
Background Due to the heterogeneity of breast cancer (BRCA) and the limited therapeutic efficacy in specific molecular subtypes, identifying new and effective therapeutic targets remains an urgent clinical need. The transcription factor SALL2 has been shown to play distinct roles in tumorigenesis and progression, but its specific role in BRCA remains unclear. Therefore, this study investigates the effects of SALL2 on BRCA progression.Methods SALL2 expression in the TCGA and clinical BRCA tissue samples was analyzed. Cell and animal models were established to validate the effects of SALL2 on BRCA cell proliferation, migration, and tumorigenicity. Molecular experiments were performed to investigate the association between NSUN2 and SALL2 in BRCA and cellular ferroptosis regulation by SALL2.Results SALL2 is significantly overexpressed in BRCA tissues and cell lines, knocking down SALL2 reduces BRCA cell growth, migration, and tumorigenesis in vitro and in vivo models. The m5C methyltransferase NSUN2, together with the reader protein YBX1, modifies SALL2 mRNA with m5C, which stabilizes the transcript. SALL2 then acts as a transcriptional repressor by binding directly to the promoter region of ACSL4 and inhibiting its transcriptional activity. Suppression of SALL2 activates ferroptotic cell death by lowering the antioxidant defences of GPX4/SLC7A11 and increasing the expression of ACSL4 and COX2. Ferroptosis inhibitors can reverse the growth-inhibiting effects caused by SALL2 depletion.Conclusion In BRCA, SALL2 is precisely regulated by m5C RNA methylation modification, further promoting cancer progression by inhibiting cell ferroptosis, suggesting its potential as a prognostic biomarker and a target for therapy.
Loss of the PTEN tumor suppressor gene is a common molecular feature in advanced prostate cancer and is associated with activation of the PI3K/AKT signaling pathway, which controls cell growth and survival. Despite major advances in the treatment of metastatic castration-sensitive prostate cancer (mCSPC), patients with PTEN-deficient tumors represent an aggressive subgroup with poorer clinical outcomes and limited targeted therapeutic options. Capivasertib is a selective oral AKT inhibitor designed to suppress downstream signaling from PI3K pathway activation. We highlight the recent results from the Phase III CAPItello-281 trial (NCT04493853) demonstrating that the addition of capivasertib to abiraterone acetate and androgen deprivation therapy (ADT) significantly improved radiographic progression-free survival in patients with PTEN-deficient mCSPC, leading to the FDA-approval of this regimen. Notable adverse events in the cabavisertib arm included hyperglycemia, diarrhea, and rash. CAPItello-281 addresses a significant unmet need for PTEN-deficient mCSPC, suggesting AKT inhibition as a potential new targeted treatment strategy for a sub-population with poor prognosis.
Introduction Lenvatinib is a first-line therapy for hepatocellular carcinoma (HCC), but its clinical efficacy is limited by drug resistance. ABHD17C, a depalmitoylation enzyme involved in HCC progression, has not been investigated in lenvatinib response. This study aimed to determine whether ABHD17C regulates the anti-tumor efficacy of lenvatinib in HCC.Methods Published single-cell RNA sequencing (scRNA-seq) data were analyzed to characterize ABHD17C expression in the HCC tumor microenvironment. Functional assays were performed in HCC cell lines to evaluate the effects of lenvatinib and ABHD17C modulation. The findings were validated using HCC xenograft mouse models and patient-derived tumor organoids.Results scRNA-seq analysis showed that ABHD17C is associated with an immunosuppressive tumor microenvironment characterized by reduced CD8⁺ T cell infiltration, increased T cell exhaustion, and abnormal intercellular communication. In vitro, lenvatinib inhibited proliferation, migration, and invasion while inducing apoptosis and cell cycle arrest in HCC cells. These effects were significantly attenuated by ABHD17C overexpression but enhanced by ABHD17C depletion. In vivo, ABHD17C-overexpressing xenografts were less responsive to lenvatinib, exhibiting increased tumor growth and reduced apoptosis. Similarly, in patient-derived organoids, ABHD17C overexpression diminished lenvatinib efficacy. Notably, lenvatinib reduced ABHD17C expression in organoids, suggesting potential feedback regulation.Conclusion ABHD17C promotes an immunosuppressive tumor microenvironment and attenuates the anti-tumor effects of lenvatinib in HCC. Targeting ABHD17C may represent a potential strategy to enhance lenvatinib sensitivity and improve therapeutic outcomes.
SEC61G, the γ subunit of the Sec61 translocon, has long been regarded as a passenger co-amplification target of EGFR on chromosome 7p11.2. Recent studies have revealed its independent oncogenic functions across multiple cancers. This review proposes a mechanism-based classification of SEC61G oncogenic activities: (1) immune checkpoint regulation via canonical translocation; (2) aberrant calcium signaling; and (3) non-canonical mechanisms independent of channel functions. We further delineate the pan-cancer expression and CRISPR-Cas9 dependency landscape, highlighting a dual “high expression, high dependency” profile in cervical squamous cell carcinoma. We distinguish current pore-targeting Sec61 inhibitors from subunit-specific strategies and propose future directions including PROTAC degraders and PPI inhibitors. Our review identifies SEC61G as a pan‑cancer prognostic biomarker and immunotherapy response predictor, with mechanistic evidence supporting its driver roles in glioblastoma, non‑small cell lung cancer, and colorectal cancer, whereas associations in other cancers remain correlative and require further validation.
BACKGROUND:CDK4/6 inhibitors (CDK4/6i) represent the standard treatment for HR+/HER2- ABC. The study assessed the efficacy and safety profiles of CDK4/6i from first-line (1 L) to third-line (3 L) in patients with HR+/HER2- ABC from high-altitude versus low-altitude regions. MATERIALS:HR+/HER2- ABC patients who received CDK4/6i were enrolled from four cancer centers in China. RESULTS:A total of 350 patients were eligible for the study, involving 268 from the low-altitude group and 82 from the high-altitude group. In the 1 L, objective response rate (ORR, 23.7% versus 5.3%, p = 0.01), clinical benefit rate (CBR, 88.1% versus 57.9%, p < 0.0001), and median progression-free survival (PFS, 42.1 months versus 15.2 months, p = 0.001) in the low-altitude group were superior to those in the high-altitude group. In the second-line treatment, CBR in the low-altitude group was higher (87.5% versus 48.0%, p = 5.3E-4). The ORR (20.8% versus 4.0%, p = 0.08) and PFS (15.8 months versus 8.2 months, p = 0.11) were not significantly different. In the 3 L settings, no significance was observed in PFS (5.2 months versus 5.8 months, p = 0.45), ORR (16.5% versus 21.1%, p = 0.74), and CBR (47.1% versus 47.4%, p = 1). The incidence of anemia (43.9% versus 28.3%, p = 0.01), ≥grade 3 anemia (9.8% versus 1.9%, p = 3.10E-03), ≥grade 3 thrombocytopenia (9.8% versus 1.9%, p = 3.10E-03), ≥grade 3 ALT (6.1% versus 0.4%, p = 3.10E-03) and AST (7.3% versus 1.9%, p = 0.02) dysfunction occurred more frequently in the high-altitude group. CONCLUSION:Patients with HR+/HER2- ABC in the high-altitude region experienced inferior survival outcomes and individualized tolerability to CDK4/6i, which may inform scientific research and the management of CDK4/6i in Chinese patients with HR+/HER2- ABC.
Background Leukotrienes are bioactive lipid mediators produced via the 5-lipoxygenase (5-LO) pathway and are essential for inflammatory signaling in the tumor microenvironment (TME), playing roles in angiogenesis, immune modulation and metastatic progression.Objective This review evaluates the role of leukotriene signaling in cancer progression and highlights biomarker-guided therapeutic strategies targeting these pathways in the TME.Methods A narrative review of preclinical, clinical, and epidemiological studies was performed, with prespecified inclusion criteria and prioritization of recent evidence.Results Leukotriene-mediated signaling correlates with biomarkers such as CysLT1 receptor expression, β-catenin activation, and HIF-1α signaling. In preclinical models, pharmacological agents including montelukast, zileuton, and FLAP antagonists suppress tumor growth, and restore apoptotic signaling; current clinical evidence remains largely observational and pharmacoepidemiologic.Conclusion Targeting this pathway represents a promising avenue in oncology, with potential to enhance precision medicine through biomarker-guided patient stratification. Further clinical validation is warranted to translate these findings into therapeutic benefit.
Background Osteosarcoma survival rates have not improved significantly in decades, as complex gene mutations and intratumoral heterogeneity hinder new therapy development. To exploit the widespread chromosomal instability in osteosarcoma, we investigated targeting the essential mitotic motor protein KIF18A.Materials Two whole-genome-doubling clones derived from the near-diploid SJSA1 osteosarcoma cell line were used to evaluate sensitivity to KIF18A knockout or pharmacological inhibition. The traditional osteosarcoma cell lines U2OS and MG63 were included in the study of the KIF18A inhibitor at both the cellular and xenograft (nude mice) levels.Results Depletion of KIF18A significantly reduced cell viability, survival, and proliferation in the SPT cell, but not in the parental SJSA1 cell. Loss of KIF18A expression led to aberrant spindle assembly and mitotic delay through the activation of spindle assembly checkpoint (SAC) signaling. Therefore, the deficiency of SAC rescued the SPT cell growth. We then tested one of the latest KIF18A inhibitors, AM-1882, in SPT, U2OS, and MG63 cells. It showed potent anti-cancer activity and disruption of spindle assembly activity, just like the KIF18A knockout. In the mouse xenograft model, AM-1882 also apparently prevented tumor growth and, notably, did not show any toxicity when compared with chemotherapeutic drugs.Conclusion Overall, our study demonstrated that KIF18A is a promising therapeutic target in osteosarcoma. The novel inhibitor AM-1882 offers exceptional anti-tumor efficacy paired with a favorable, low-toxicity safety profile.
Background Colorectal cancer (CRC) ranks among the most prevalent malignancies globally, and radiotherapy remains a critical treatment modality. However, its efficacy is frequently compromised by acquired radioresistance. The endoplasmic reticulum chaperone protein BIP plays a pivotal role in regulating radioresistance by coordinating the balance between protective autophagy and apoptosis, though the regulatory roles of circular RNAs (circRNAs) in this process remain poorly understood.Materials Differentially expressed circRAB5A (hsa-circ-0123297) was identified from the GSE186940 dataset. Its expression was validated in radioresistant CRC clinical samples and cell lines. Mechanistic investigations involved ADAR1 binding assays, circRAB5A gain/loss-of-function studies, autophagy-apoptosis profiling, ubiquitination analysis, TRIM21-mediated degradation assays, and in vivo xenograft models.Results & conclusion CircRAB5A was significantly downregulated in radioresistant CRC clinical samples and cell lines. This downregulation was driven by ADAR1, which suppressed circRAB5A biogenesis by binding to Alu Jo/Jr elements. Functional assays showed circRAB5A depletion conferred radioresistance in CRC cells by promoting protective autophagy and inhibiting apoptosis. Mechanistically, circRAB5A destabilized BIP by enhancing TRIM21-mediated ubiquitination. The circRAB5A/BIP axis further modulates the autophagy-apoptosis balance through the p-Akt/Beclin1 signaling pathway, thereby influencing radiosensitivity. In vivo xenograft experiments demonstrated that stable knockdown of circRAB5A attenuated the anti-tumor effects of radiation, whereas knockdown of BIP sensitized CRC cells to radiotherapy even at low doses. Collectively, the ADAR1/circRAB5A/BIP molecular circuitry governs CRC radioresistance by regulating the autophagy-apoptosis balance. Our findings highlight that low circRAB5A expression may serve as a potential biomarker for radioresistance, and that targeting this axis, particularly BIP, represents a promising strategy for overcoming radioresistance in CRC.
BACKGROUND:A subset of patients with chronic myelomonocytic leukemia (CMML) carries NRAS mutations, which are associated with shorter overall survival and an increased risk of transformation to acute myeloid leukemia. However, the effects of NRAS mutations on the bone marrow microenvironment (BME) remain unclear. METHODS:We used a CMML mouse model driven by a single Nras G12D allele mutation to investigate alterations in the BME and the potential role of CD69 in immune suppression. Nras G12D-mutated CMML mice were treated with an anti-CD69 monoclonal antibody. Flow cytometry, hematoxylin-eosin staining, and RNA sequencing were performed to evaluate treatment-related changes. RESULTS:Nras G12D-mutated CMML mice showed increased infiltration of regulatory T (Treg) cells and CD69+ T cells in the BME, whereas CD69 expression on peripheral blood T cells remained lower than that on bone marrow T cells. Anti-CD69 monoclonal antibody treatment was associated with reduced generation of granulocyte-macrophage progenitor cells, prolonged survival, and decreased Treg accumulation in the BME. CONCLUSION:Our findings suggest that CD69 may serve as a biomarker of BME immunological dysfunction in CMML.
BACKGROUND:Pancreatic adenocarcinoma is a highly aggressive cancer with very limited treatment options. This study aimed to optimize the efficacy of a previously developed tumor immunotherapy for the treatment of this disease and its recurrences. METHODS:Mouse models of pancreatic and colon adenocarcinoma were established using Panc02 and MC38 cells, respectively. Tumors were treated by intratumoral administration of MBTA, a formulation containing resiquimod, poly(I:C), LTA, anti-CD40 antibody, and mannan-BAM (a phagocytosis-stimulating mannan anchored to the tumor cell membrane via a biocompatible membrane anchor, BAM). Multiple variants of the therapy were tested, differing in composition and timing, including treatment of recurrences. RESULTS:Intratumoral MBTA immunotherapy administered using an optimized 5 × 2 schedule resulted in an 87.5% survival rate in mice bearing subcutaneous Panc02 tumors. MBTA immunotherapy also effectively treated spontaneous local Panc02 recurrences that developed in a small subset of mice. High efficacy of MBTA was further confirmed in a murine model of colon adenocarcinoma. CONCLUSION:These findings suggest that MBTA is a promising therapeutic approach for primary and recurrent pancreatic adenocarcinoma, with potential for broader clinical application.
Macroautophagy (autophagy) enables cellular stress adaptation by degrading damaged components; ULK1, a serine/threonine kinase, initiates this process in response to nutrient and energy cues. While autophagy is well studied, few investigations have directly tested ULK1 in cancer progression. Emerging functional data across numerous cancers indicate that ULK1 can promote or restrain malignant behavior through both autophagy-dependent and autophagy-independent mechanisms, modulating mitochondrial quality, anoikis escape, invasion, therapy adaptation, and immune visibility. Pharmacology has advanced from early ULK1/2 inhibitors to structure-guided and machine learning-derived inhibitors with improved potency and selectivity. The first clinical agent, DCC-3116, demonstrates on-target engagement with acceptable tolerability and is being evaluated in combinations where therapy induces autophagy. Here, we review ULK1 as a regulator of cancer progression, synthesizing pan-cancer clinical and functional evidence alongside the evolving pharmacology of ULK1 modulation to define the settings in which its targeted inhibition may be most effectively translated.
Objective To clarify the clinical significance and biological function of retinol dehydrogenase-11 (RDH11) in prostate cancer (PCa) and to elucidate the downstream signaling mechanism through which it drives tumor progression.Methods Public and in-house transcriptomic data were mined to compare RDH11 levels between PCa and matched normal tissues. RDH11 was stably silenced (shRDH11) or over-expressed (oeRDH11) in PC-3, DU145, and LNCaP cells; cell proliferation, migration, and invasion were quantified with CCK-8 and Transwell assays. RNA-seq and gene set enrichment analysis (GSEA) were performed to screen downstream targets and pathways. Rescue experiments in vitro and in vivo were used to confirm the mechanism.Results RDH11 levels were markedly elevated in human PCa tissues and cell lines. Silencing RDH11 hindered PCa cell proliferation, migration, and invasion, whereas its overexpression had the opposite effects. Mechanistically, we identified the tropomyosin receptor kinase (TRKA) and STAT3 signaling pathway as the downstream gene and pathway of RDH11. Rescue assays using PC3, DU145, and LNCaP cells demonstrated that RDH11 facilitated PCa progression by upregulation of TRKA and the activation of STAT3 signaling. In vivo studies further confirmed that RDH11 overexpression enhanced prostate tumor growth, whereas TRKA knockdown counteracted the oncogenic effects of RDH11.Conclusion RDH11 promotes the development of PCa through the upregulation of TRKA and activation of the STAT3 signaling pathway.
