Search Results (1,029)

In recent years, the scientific community has increasingly delved into the study of the interaction between the nervous system and tumors, revealing that the nervous system not only regulates bodily functions under physiological conditions, but also assumes a vital part in the emergence and progression of tumors. Research has demonstrated that the extensive neural network directly regulates tumor progression and can influence tumors by modulating the tumor microenvironment and immune system. Moreover, tumors induce neural networks to provide favorable conditions for their proliferation and metastasis. In the above process, neurotransmitters play a vital role. They directly act or bind to their receptor, activating various classical signaling pathways, among which are PI3K/AKT, MEK/ERK, and WNT/β-catenin, to facilitate tumor advancement. Therefore, this study systematically reviews the regulatory mechanisms of neurotransmitters and their receptors in the advancement of cancer, along with the utilization of targeted drugs. At the same time, we also analyzed that targeting specific receptor subtypes may produce more significant therapeutic effects in different types of cancer. Additionally, this research further explores the limitations of neurotransmitter-based drugs currently used in clinical cancer treatment. In summary, the field of cancer neuroscience is rapidly advancing, constantly revealing the regulatory effects of neurotransmitters on tumor progression and their specific molecular mechanisms, providing broad application prospects for future clinical therapy. Full article

Hepatocellular carcinoma (HCC) is a deadly liver cancer characterized by dysregulated signaling and aberrant cell-cycle control. The FGFR4/FGF19 pathway is dysregulated in HCC and other cancers. Inhibitors targeting the FGF19/FGFR4 pathway, including the FGF19/FGFR4 inhibitor FGF401, have been investigated in HCC and other cancers; however, nearly all patients who initially respond eventually develop resistance shortly after starting therapy, highlighting the urgent need for new treatment strategies to overcome drug resistance. In the present study, we report that chronic treatment of the FGF19/FGFR4-expressing HCC25−0705A line with FGF401 led to acquired resistance. FGF401-resistant tumors exhibited upregulation of FGFRs and activation of the PI3K/AKT/mTOR/p70S6K pathway. Combination therapy with FGF401 and the mammalian target of rapamycin (mTOR) inhibitor everolimus (FGF401/everolimus) resulted in more complete tumor growth inhibition, delayed the onset of resistance, and prolonged overall survival (OS) in mice bearing orthotopic HCC tumors. The FGF401/everolimus combination effectively suppressed tumor cell proliferation; promoted apoptosis; reduced tumor hypoxia via blood vessel normalization; and downregulated key proteins involved in proliferation, survival, metastasis, and angiogenesis. These preclinical findings provide a strong rationale for clinical trials combining FGFR4 and mTOR inhibitors in HCC patients with FGF19/FGFR4/mTOR-dependent tumors. Full article

Background: Tumor-associated macrophages (TAMs) are essential regulators of the glioblastoma (GBM) microenvironment; their functional heterogeneity and interaction networks are not fully elucidated. We identify RNF135 as a novel TAM-enriched gene associated with immune activation and adverse prognosis in GBM. Methods: To evaluate RNF135’s expression profile, prognostic significance, and functional pathways, extensive transcriptome analyses from TCGA and CGGA cohorts were conducted. The immunological landscape and cellular origin of RNF135 were outlined using single-cell RNA-seq analyses and bulk RNA-seq immune deconvolution (MCP-counter, xCell and ssGSEA). Cell–cell communication networks between tumor cells and RNF135-positive and -negative tumor-associated macrophage subsets were mapped using CellChat. Results: RNF135 predicted a poor overall survival and was markedly upregulated in GBM tissues. Functional enrichment analyses showed that increased cytokine signaling, interferon response, and innate immune activation were characteristics of RNF135-high samples. Immune infiltration profiling showed a strong correlation between the abundance of T cells and macrophages and RNF135 expression. According to the single-cell analyses, RNF135 was primarily expressed in TAMs, specifically in proliferation, phagocytic, and transitional subtypes. RNF135-positive TAMs demonstrated significantly improved intercellular communication with aggressive tumor subtypes in comparison to RNF135-negative TAMs. This was facilitated by upregulated signaling pathways such as MHC-II, CD39, ApoE, and most notably, the CCL signaling axis. The CCL3/CCL3L3–CCR1 ligand–receptor pair was identified as a major mechanistic driver of TAM–TAM crosstalk. High RNF135 expression was also linked to greater sensitivity to Selumetinib, a selective MEK1/2 inhibitor that targets the MAPK/ERK pathway, according to drug sensitivity analysis. Conclusions: RNF135 defines a TAM phenotype in GBM that is both immunologically active and immunosuppressive. This phenotype promotes inflammatory signaling and communication between cells in the tumor microenvironment. Targeting the CCL–CCR1 axis or combining RNF135-guided immunomodulation with certain inhibitors could be a promising therapeutic strategies for GBM. Full article

Small molecule inhibitors targeting BRAF mutations at V600 and downstream MEK represent a significant advancement in treating BRAF-mutant melanoma. However, resistance mechanisms, often involving reactivation of the MAPK pathway via ERK1/2, limit their efficacy. The ERK1/2 inhibitor ravoxertinib (GDC0994) was tested on melanoma cell lines with and without resistance to BRAFi or BRAFi + MEKi. Short-term assays evaluated cell viability, apoptosis induction, and pathway modulation via Western Blot, while long-term effects were assessed using a colony formation assay. Resistant and parental melanoma cells responded to long-term ERKi treatment with reduced growth, independent of sensitivity to BRAF or MEK inhibitors. Adding ERKi to BRAFi/MEKi significantly enhanced apoptosis and growth inhibition, particularly in resistant lines. Although ravoxertinib alone showed limited antitumor activity, its combination with BRAFi/MEKi yielded substantial benefits, especially in chronic settings. These findings suggest that combinatorial regimens incorporating ERK inhibitors represent a promising therapeutic strategy for BRAF-mutant melanoma. Full article

Extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors show therapeutic potential in triple-negative breast cancer (TNBC), but resistance through compensatory signaling limits their efficacy. We previously identified the secretory carrier membrane protein 3 (SCAMP3) as a regulator of TNBC progression and ERK1/2 activation. Here, we investigated the role of SCAMP3 in ERK1/2 signaling and therapeutic response using TMT-based LC-MS/MS phosphoproteomics of wild-type (WT) and SCAMP3 knockout (SC3KO) SUM-149 cells under basal conditions, after epidermal growth factor (EGF) stimulation, and during ERK1/2 inhibition with MK-8353. A total of 4408 phosphosites were quantified, with 1093 significantly changed. SC3KO abolished residual ERK activity under MK-8353 and affected the compensatory activation of oncogenic pathways observed in WT cells. SC3KO reduced the phosphorylation of ERK feedback regulators RAF proto-oncogene serine/threonine-protein kinase Raf-1 (S43) and the dual-specificity mitogen-activated protein kinase kinase 2 (MEK2) (T394), affected other ERK targets, including nucleoporins, transcription factors, and metabolic enzymes triosephosphate isomerase (TPI1) (S21) and ATP-citrate lyase (ACLY) (S455). SCAMP3 loss also impaired the mammalian target of rapamycin complex I (mTORC1) signaling and disrupted autophagic flux, evidenced by elevated sequestosome-1 (SQSTM1/p62) and microtubule-associated protein light chain 3 (LC3B-II) with reduced levels of the autophagosome lysosome maturation marker, Rab7A. Beyond ERK substrates, SC3KO affected phosphorylation events mediated by other kinases. These findings position SCAMP3 as a central coordinator of ERK signaling and autophagy. Our results support SCAMP3 as a potential therapeutic target to enhance ERK1/2 inhibitor clinical efficacy and overcome adaptive resistance mechanisms in TNBC. Full article

Ovarian cancer (OCa) remains the most lethal gynecologic malignancy in the United States, with low-grade serous and mucinous subtypes frequently driven by KRAS mutations. These mutations activate downstream MAPK and PI3K/AKT signaling pathways, contributing to tumor progression and resistance to therapy. Although the MEK inhibitor trametinib is used to target these pathways, its efficacy is limited in KRAS-mutant OCa due to compensatory activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) axis. In this study, we evaluated the therapeutic potential of combining trametinib with EC359, a selective LIFR inhibitor, in Ras/Raf-driven OCa models. EC359 significantly reduced cell viability, clonogenic survival, and induced cell death via ferroptosis in vitro. Mechanistic studies revealed that EC359 suppressed trametinib-induced activation of LIFR downstream signaling. RNA-seq analysis showed that combination therapy downregulated mitochondrial translation and MYC target genes while upregulating apoptosis-related genes. In vivo, EC359 and trametinib co-treatment significantly reduced tumor growth in xenograft and PDX models without inducing toxicity. Our studies identify LIFR signaling as a critical vulnerability in Ras/Raf-mutant and low grade serous OCa. Further, it provides strong preclinical rationale for EC359 and trametinib combination therapy as a new therapeutic strategy for treating Ras/Raf-driven OCa and low-grade serous OCa. Full article

Background/Objectives: Colorectal carcinoma (CRC) is among the most commonly diagnosed cancers in both men and women. Although CRC mortality is generally decreasing, new therapeutic options are needed for unresponsive subgroups of CRC patients. Methods: A series of known and new tyrphostin derivatives was tested for their efficacy against three CRC cell lines with varying KRAS, p53, and/or BRAF statuses. Growth inhibition, apoptosis induction, and inhibition of EGFR and VEGFR-2 were investigated. Results: Tyrphostin A9, the known RG13022-related tyrphostin 1a and its dichlorido(p-cymene)ruthenium(II) complex 1b, and the new SF₅-substituted compounds 2a and 2b showed selective antiproliferative activity against KRAS-mutant HCT-116 CRC cells expressing wildtype p53, while p53-knockout HCT-116 and KRAS-wildtype BRAF/p53-mutant HT-29 CRC cells were distinctly less sensitive. In HCT-116 cells, only tyrphostin A9 increased mRNA expression of caspases 3 and 8, as well as the kinases MEK1 and MEK2, whereas 2a reduced caspase 8 mRNA levels. Tyrphostin A9 increased caspase 3 activity and induced apoptosis in HCT-116 p53-wildtype cells while simultaneously inhibiting the receptor tyrosine kinases EGFR and VEGFR-2 at low nanomolar concentrations. Conclusions: Tyrphostin A9 could be a promising therapeutic option for the treatment of KRAS-mutant CRC that expresses wildtype p53. Full article

Objectives: We conducted a systematic review of clinical trials and case reports analyzing the safety of the currently approved BRAF and MEK inhibitors in adults with cutaneous melanoma (CM), and a meta-analysis to estimate the pooled prevalence of treatment-related adverse events (TRAEs). Methods: We systematically searched six databases for studies published since 2009. The TRAE absolute frequencies reported in primary studies were aggregated using the Metaprop command in Stata 17, which calculates 95% confidence intervals (CIs) incorporating the Freeman–Tukey double arcsine transformation of proportions to stabilize variances within random-effect models. Methodological quality was assessed using the RoB 2 tool for randomized controlled trials (RCTs) and the ROBINS-I tool for non-randomized studies. Results: Twelve RCTs, thirteen prospective cohort studies (PCSs), and ten case reports were included. Meta-analysis was feasible for two regimens: vemurafenib 960 mg monotherapy and dabrafenib 150 mg twice daily plus trametinib 1–2 mg daily. The most common TRAEs during vemurafenib treatment were musculoskeletal and connective-tissue disorders (24%, 95% CI: 6–41%, p = 0.01), with arthralgia as the most prevalent (44%, 95% CI: 29–59%, p < 0.001), followed by rash (39%, 95% CI: 22–56%, p < 0.001). The most common TRAEs during dabrafenib plus trametinib were constitutional toxicities (classified in CTCAE as ‘General disorders and administration site conditions’; 25%, 95% CI: 14–37%, p < 0.001), with fatigue as the most prevalent (47%, 95% CI: 38–56%, p < 0.001), followed by pyrexia (40%, 95% CI: 26–54%, p < 0.001). Squamous cell carcinoma and keratoacanthoma were among the most frequent grade ≥ 3 cutaneous adverse events observed with vemurafenib therapy. Conclusions: Although additional large-scale studies are needed to corroborate these findings, each treatment has a distinct toxicity profile that should be considered when developing personalized risk-stratified treatment plans and in guiding healthcare resource allocation in melanoma care. Full article

Background: Alpiniae oxyphyllae-Saposhnikovia divaricata (AS), a traditional Chinese dietary supplement, exhibits potential therapeutic effects against diabetic kidney disease (DKD), though its active compounds and mechanisms require elucidation. Methods: Animal experiments integrated with UHPLC-QE-MS, bioinformatics, and experimental validation were employed to investigate AS’s pharmacodynamic basis against DKD. Results: Thirty-nine compounds were identified in AS, including four key flavonoids (daidzein, kaempferol, tectoridin, baicalin). Bioinformatics screening revealed 516 potential AS targets from PubChem/TCMSP/ETCM databases. Analysis of the GEO dataset (GSE30529) identified 482 DKD-related differentially expressed genes (DEGs). Venny 2.1 analysis yielded 42 co-DEGs and 6 co-core DEGs. Functional enrichment (GO/KEGG/GSEA) demonstrated AS’s modulation of apoptosis and extracellular matrix (ECM) pathways via these DEGs. ROC profiling and renal single-cell sequencing highlighted FOS as a specific regulator of podocyte apoptosis in DKD. Molecular docking confirmed stable binding between the four flavonoids and FOS. Experimentally, AS significantly suppressed expression of ECM-related proteins (Col-IV, LN, IL-6, IL-17) and pro-apoptotic proteins (Bax, Caspase-3), while restoring anti-apoptotic Bcl-2 levels and inhibiting phosphorylation of MEK4, JNK1, c-Jun, and FOS in DKD mice. Conclusion: This study elucidates that AS alleviates DKD by inhibiting the MAPK/FOS pathway, thereby attenuating podocyte apoptosis and ECM accumulation. These findings establish a foundation for targeted AS therapy in DKD. Full article

Entosis is a form of cell-in-cell interaction observed in epithelial cancers, characterized by the internalization of one cell into another. This process is initiated by cell detachment, cadherin-mediated homotypic adhesion, and the formation of an entotic vacuole. Mechanistically, entosis is driven by Rho/ROCK signaling and actomyosin contractility in the invading (inner) cell, which becomes stiffer and is pulled into the softer host (outer) cell. A functional assay using differently stained cell populations allows for the assessment of pharmacological interventions on either the inner or outer cell during entosis. In this study, we investigated the impact of MEK pathway inhibition on entosis in two epithelial cancer cell lines, BxPC3 (pancreatic cancer) and MCF7 (breast cancer). BxPC3 cells, which rely on adhesion, exhibited a significant reduction in entotic index upon MEK inhibition. In contrast, MCF7 cells showed no selectivity of entosis to three different MEK inhibitors. These findings suggest cell-type-specific regulation of entosis, potentially linked to differences in protrusion formation mechanisms and upstream Ras signaling pathways previously implicated in cancer cell motility. Full article

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and the lung is one of the most frequent metastatic sites for HCC. In this study, we aimed to identify a mild active substance in Morus alba L. that can inhibit the pulmonary metastasis of HCC and reduce the drug resistance of clinical therapies. Further deepen the understanding of the anti-cancer functions of the mulberry active substances. In this study, we have screened and identified a flavonoid compound extracted from the root bark of the Morus alba L. named Kuwanon A (KA). Our research demonstrated that KA directly targeted the YWHAB (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta) and mediated its dimer dissociation. Thereby inhibiting the MAPK pathway and affecting downstream biological functions, including cell cycle arrest and migration/invasion inhibition. The experiment results proved that KA could inhibit the proliferation and metastasis of highly metastatic HCC cells both in vitro and in vivo. Additionally, when KA was combined with the clinical drug sorafenib, it exhibited a synergistic effect in inhibiting HCC cell proliferation, migration, and invasion. In conclusion, KA demonstrated a favorable anti-tumor effect in HCC cells. Full article

Skin health is significantly impacted by factors such as melanin production, UV-induced photodamage, and wound healing. Excessive melanin leads to hyperpigmentation, while UVA radiation accelerates skin aging and oxidative stress. This study investigated the multi-functional dermatological potential of S strain LS-derived cell-free supernatant (CFS-LS) to address these concerns. Our findings demonstrate that CFS-LS effectively inhibits melanogenesis in B16F10 cells. It significantly reduced α-MSH-induced melanin synthesis, comparable to arbutin, by downregulating key melanogenic enzymes (tyrosinase, TRP-1, and TRP-2) and regulatory proteins (p-CREB, MITF, SOX9, and SOX10). Mechanistically, CFS-LS suppressed the phosphorylation of MEK, ERK, p38, and JNK, indicating a dual inhibitory effect on both PKA/CREB and MAPK pathways. Furthermore, CFS-LS mitigated UVA-induced photodamage in HaCaT cells by significantly reducing intracellular reactive oxygen species and suppressing the downstream phosphorylation of p53 and α-MSH levels. It also restored UVA-suppressed Nrf-2 and HO-1 expression, enhancing cellular antioxidant defenses. Lastly, CFS-LS promoted skin wound healing by significantly enhancing HaCaT cell migration in a scratch assay, associated with increased p-MEK1/2 and p-ERK1/2 levels, and notably elevated collagen type I synthesis. Collectively, these results highlight CFS-LS as a potent multi-functional agent for skin protection and repair, with significant potential for cosmetic and therapeutic applications. The active components of CFS-LS warrant further investigation. Full article

Background: This study investigates how sorafenib induces toxicity in glomerular cells and examines the protective role of 8,9-epoxyeicosatrienoic acid (8,9-EET) analogs in reducing this kidney damage. Methods: Human renal mesangial cells (HRMCs) and podocytes were treated with no treatment, sorafenib alone, or sorafenib combined with 8,9-EET analogs. Cell viability and apoptosis were measured in both cell types. Results: Sorafenib (1–10 µM) lowered cell viability and increased caspase 3/7 activity in a dose-dependent way in HRMCs and podocytes. Five of twenty 8,9-EET analogs significantly enhanced cell survival and decreased apoptosis. RNA sequencing showed that sorafenib altered 1244 genes, including those involved in cell cycle and the Raf/MEK/ERK pathway. The 8,9-EET analog MDB-52a raised ANGPTL4 levels, linked to metabolism and vascular health, and reduced ACTA2, which could activate protective pathways. Nephroseq data correlated these gene changes with glomerulosclerosis. Conclusions: MDB-52 appears to counteract gene disruptions and protect against sorafenib-induced kidney damage. Overall, 8,9-EET analogs targeting glomerular cells could be potential therapeutic agents to lessen sorafenib-related nephrotoxicity. Full article

Low-grade-serous ovarian carcinomas (LGSOC) are rare tumors characterized by a high recurrence rate and limited treatment options. Most LGSOC are estrogen receptor (ER)-positive and demonstrate alterations in the RAS/MAPK pathway. Avutometinib is a dual RAF/MEK clamp, whereas defactinib and VS-4718 are focal adhesion kinase (FAK) inhibitors. Fulvestrant is an ER antagonist/degrader. We assessed the preclinical efficacy of fulvestrant, avutometinib + VS-4718 (FAKi), and the triple combination in a chemotherapy/aromatase inhibitor-resistant LGSOC patient-derived tumor xenograft (PDX) model. Tissue obtained from a LGSOC patient wild-type for KRAS/NRAS/BRAF mutations in progression after chemotherapy/anastrozole was transplanted into female CB17/lcrHsd-Prkdc/SCID mice (PDX-OVA(K)250). The animals were treated with either saline/control, fulvestrant, avutometinib/FAKi, or the triple combination of avutometinib/FAKi/fulvestrant. Avutometinib and FAKi were given five-days on and two-days off through oral gavage. Fulvestrant was administered subcutaneously weekly. Mechanistic studies were performed ex vivo using Western blot assays. Animals treated with the triple combination demonstrated stronger tumor growth inhibition compared to all the other experimental groups including control/saline (p < 0.001), single-agent fulvestrant (p = 0.04 from day eight and onwards), and avutometinib/FAKi (p = 0.02 from day 18). Median survival for mice treated with saline/control was 29 days while mice in all other experimental groups were alive at day 60 (p < 0.0001). Treatment was well tolerated across all experimental treatments. By Western blot, exposure of OVA(K)250 to the triple combination demonstrated a decrease in phosphorylated MEK (p-MEK) and p-ERK levels. The addition of fulvestrant to avutometinib/FAKi is well tolerated in vivo and enhances the antitumor activity of avutometinib/FAKi in a LGSOC-PDX model with acquired resistance to chemotherapy/aromatase inhibitors. These results support the clinical evaluation of avutometinib/defactinib in combination with fulvestrant or an aromatase inhibitor in patients with recurrent LGSOC. Full article

High-grade serous ovarian cancer (HGSOC) is an aggressive malignancy which is often treated with platinum-based chemotherapy and PARP inhibitors (PARPi). However, PARPi resistance remains a major clinical challenge, necessitating alternative therapeutic strategies. In this study, we establish the first known patient-derived organoid models directly from PARPi-resistant HGSOC and demonstrate that they preserve the original tumor architecture and key biomarkers (EpCAM, CA125, PAX8, HER2, MEK1/2, Cyclin E1), thus providing unique preclinical models for drug testing. These organoids were used to evaluate lurbinectedin in comparison with standard carboplatin and paclitaxel. While lurbinectedin showed comparable apoptotic effects to paclitaxel and superior activity to carboplatin, it induced chromosomal breaks to different extents in different cell lines, suggesting a distinct mechanism of action. Importantly, this work does not advocate for lurbinectedin as a superior therapy but, rather, demonstrates the utility of organoid models in uncovering drug-specific genomic effects. Our findings underscore the critical need for expanded testing using clinically relevant models to identify more effective strategies against PARPi-resistant disease. Full article