Oncology Research最新文献

Objectives: Acquired resistance to paclitaxel represents a critical barrier to the effective chemotherapy of non-small cell lung cancer (NSCLC). The present study aimed to elucidate the molecular and pharmacological mechanisms promoting paclitaxel resistance in NSCLC and to explore potential strategies for overcoming this resistance.

Methods: Here, we report an integrated pharmacological and analytical approach to quantify paclitaxel disposition and overcome resistance in a A549/TAX cell model (paclitaxel-resistant A549 cells).

Results: Cell counting kit-8 (CCK-8) assay, colony formation, and apoptosis assays confirmed that A549/TAX cells exhibited marked resistance to paclitaxel relative to parental A549 cells. Based on transcriptome profiling by RNA sequencing analysis and validation by western blotting assay, we found that the expression of the ATP-binding cassette subfamily B member 1 (ABCB1) (the encoded protein is termed P-glycoprotein) was significantly upregulated in resistant cells. By using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we demonstrated that ABCB1 overexpression promotes enhanced efflux of intracellular paclitaxel, thereby lowering its cytotoxic accumulation. Genetic silencing of ABCB1 or pharmacological inhibition with the specific P-glycoprotein modulator elacridar or tariquidar restored intracellular paclitaxel levels, as determined by UPLC-MS/MS, and synergistically decreased cell viability as observed in CCK-8 assay.

Conclusion: These findings reveal that the ABCB1-mediated drug efflux is a crucial mechanism underlying paclitaxel resistance in NSCLC cells, with UPLC-MS/MS serving as a sensitive analytical method to detect paclitaxel concentration. Inhibition of ABCB1 is a promising therapeutic strategy to resensitize resistant tumor cells to paclitaxel.

Objective: Ring finger protein 145 (RNF145), an E3 ubiquitin ligase, is significantly upregulated in hepatocellular carcinoma (HCC). However, its role in HCC remains unknown. The study aimed to investigate the functions and underlying mechanisms of RNF145 in HCC.

Methods: The role of RNF145 in HCC was investigated using data from The Cancer Genome Atlas (TCGA) and in vitro experimental assays. Its oncogenic functions were assessed using the transwell migration assay and the wound-healing assay. The molecular mechanism was explored through protein immunoprecipitation and western blot analyses. Data from public databases were analyzed to correlate RNF145 expression with clinicopathological features. Univariate and multivariate Cox analyses established RNF145 as an independent prognostic factor. Subsequently, a prognostic nomogram was constructed.

Results: RNF145 was upregulated in HCC. The expression level of RNF145 in HCC showed significant correlations with histological grade, pathological stage, and vascular invasion. Functionally, knockdown of RNF145 effectively abolished the migratory and invasive capacities of HCC cells. This pro-metastatic effect is mediated through the RNF145-driven ubiquitination and subsequent degradation of protocadherin 9 (PCDH9).

Conclusion: Our findings confirm the significant upregulation of RNF145 in HCC and promote metastasis by facilitating PCDH9 ubiquitination and degradation, highlighting its role as a prognostic biomarker and a potential therapeutic target.

Background: With a total of 1.46 million new cases and 396,792 deaths in 2022, prostate cancer is a major medical challenge around the world. Detecting and treating cancer at earlier, preferably localized stages can significantly increase survival rates. Here, a novel blood-based cancer screening as a pre-test in combination with targeted MRI imaging enabled the early diagnosis of prostate cancer.

Case description: We present the case of a 64-year-old man who participated in a prospective, interventional, multicenter cancer screening study where an immunological biopsy-based technique served as a part of a novel screening technique. This immunology technique represents a blood test exploiting two biomarkers, which may allow for the identification of individuals at an early stage of tumor development. Due to the elevated biomarker levels of Transketolase-like protein 1 (TKTL1) and Apoptoic-associated cell population 10 (Apo10), magnetic resonance imaging (MRI) was indicated for further clarification. A multiparametric MRI of the pelvis/prostate revealed an enlarged prostate gland and several suspicious lesions classified as Prostate Imaging Reporting and Data System (PI-RADS) 4 and PI-RADS 5. In further assessments, both lesions were categorized as an acinar adenocarcinoma of the prostate (Gleason Score 6, International Society of Urological Pathology (ISUP) 1, no perineural infiltration). After surgical resection, the tumor was classified histopathologically as an adenocarcinoma, pT2c pN0 (0/7), L0, V0, Pn1, R0, Gleason score 7a, ISUP 2.

Conclusions: The combination of the TKTL1/Apo10 blood test and subsequent imaging made it possible to detect a developing prostate carcinoma in a localized stage. All in all, this case report proves not just the ability but also the potential of the TKTL1/Apo10 blood test for early detection of (pre-)malignant lesions, which still present with a promising prospect for a cure.

Breast cancer is one of the most prevalent malignancies among women and comprises a heterogeneous spectrum of molecular subtypes with distinct biological behaviors. Among various regulatory molecules, sphingolipids play pivotal roles in dynamically modulating fundamental cellular processes such as proliferation, apoptosis, and metastasis through metabolic interconversions, including phosphorylation, glycosylation, and the generation of sphingosine-1-phosphate. This review aims to elucidate the mechanisms through which sphingolipid metabolism orchestrates cancer cell fate and drives breast cancer progression. Particular emphasis is placed on the balance between proapoptotic ceramides and pro-survival metabolites, such as sphingosine-1-phosphate, which collectively influence tumor growth and the therapeutic response. Additional sphingolipid species, including glucosylceramide and gangliosides (GD2, GD3, GM1, and GM3), have also been implicated in promoting breast cancer development. Furthermore, sphingolipid-based therapeutic strategies, including immunotherapy and antibody therapy, are discussed. By providing a comprehensive overview of sphingolipid metabolism, this review aims to identify novel therapeutic targets that may help overcome treatment resistance and improve clinical outcomes in breast cancer.

Background: The efficacy of standard 5-fluorouracil (5-FU) chemotherapy for colorectal cancer is limited by drug resistance and adverse effects, prompting research into esketamine, a potent ketamine variant with analgesic, antidepressant, and recently discovered anti-tumor properties, to determine if it can enhance 5-FU's chemosensitivity. This study investigates whether esketamine synergizes with 5-FU to enhance therapeutic efficacy in colorectal adenocarcinoma cell models.

Methods: We performed functional assays to evaluate proliferation (CCK-8), migration (wound healing), invasion (Transwell), and apoptosis (flow cytometry) in colorectal adenocarcinoma cell lines treated with 5-FU alone or in combination with esketamine. Transcriptomic profiling was conducted using RNA sequencing, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was employed to identify critical molecular targets and signaling networks. Protein-level validation of key pathway components was performed via western blotting.

Results: Combination therapy with esketamine and 5-FU synergistically inhibited cellular proliferation, migration, and invasion while significantly inducing apoptosis compared to monotherapy. Mechanistically, esketamine potentiated 5-FU-driven AMP-activated protein kinase (AMPK) phosphorylation, leading to inhibition of both mammalian target of rapamycin (mTOR) and hyaluronan-mediated motility receptor (HMMR).

Conclusion: Esketamine enhances 5-FU chemosensitivity in colorectal adenocarcinoma by activating the AMPK/mTOR/HMMR signaling axis, thereby suppressing tumor progression and metastatic potential. These findings position esketamine as a potential adjunctive therapy for 5-FU-based regimens, offering the dual benefit of enhancing chemotherapeutic efficacy while addressing cancer-associated comorbidities including pain and depression.

Objectives: Colorectal cancer (CRC) is a major global health burden, and Urolithin A (Uro-A) has emerged as a promising anticancer agent. This systematic review aims to synthesize current in vitro evidence on the anticancer effects of Uro-A in CRC, highlighting effective concentration ranges, exposure times, relevant outcomes, and underlying molecular mechanisms.

Methods: Following PRISMA 2020 guidelines, a systematic search was conducted in PubMed, Scopus, and Web of Science using the following strategy: (colorectal cancer) AND (urolithin a) OR (3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one). Eligibility criteria were defined by the PICO framework: (P) in vitro CRC cell models; (I) Uro-A alone or combined treatments; (C) No intervention, vehicle or other treatments; (O) Relevant anticancer outcomes of Uro-A in CRC. Only original, full-text, in vitro studies in English were included. Risk of bias was assessed using ToxRTool. A qualitative synthesis was performed due to the heterogeneity of the included studies.

Results: Fifteen studies met inclusion criteria, involving CRC cell lines (Caco-2, HCT-116, HT-29, SW480, SW620) and normal colon fibroblasts (CCD18-Co). Uro-A inhibited CRC cell proliferation, clonogenic growth, cancer stem cells properties, migration, and invasion, and induced cell cycle arrest, apoptosis, autophagy, and senescence, through modulation of key signaling pathways and proteins. Co-treatments with conventional chemotherapeutics and microbiota-derived metabolites showed additive or synergistic effects.

Discussion: The findings support Uro-A's potential as a preventive or adjuvant agent in CRC treatment. However, preclinical nature of the evidence and methodological heterogeneity hinder clinical extrapolation to in vivo contexts. Human clinical trials are necessary to overcome these limitations.

Other: This review was registered in PROSPERO (CRD420251070874) and supported by FCT/MCTES UIDP/05608/2020 and UIDB/05608/2020. Institutional.

Objective: The contribution of long non-coding RNAs (lncRNAs) associated with protein palmitoylation to the progression of hepatocellular carcinoma (HCC) remains largely unclear. This study sought to establish a prognostic signature based on palmitoylation-related lncRNAs and explore their functional implications in HCC.

Methods: RNA sequencing and clinical data for HCC and normal tissues were sourced from the Cancer Genome Atlas (TCGA). Pearson correlation analysis was used to identify lncRNAs that were co-expressed with palmitoylation-related genes. Univariate Cox regression was applied to select lncRNAs with prognostic value, followed by the construction of a predictive model using the least absolute shrinkage and selection operator (LASSO) regression. A focused analysis was performed on one key lncRNA, AC009403.1. Expression levels of the final nine lncRNAs included in the model were further validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR).

Results: A prognostic model for HCC was developed using nine palmitoylation-associated lncRNAs: AC009403.1, AC010789.1, AC026402.2, AC107021.2, AC135050.6, AL353572.4, MKLN1-AS, PRRT3-AS1, and ZNF582-AS1. This model effectively stratified patients into high- and low-risk groups exhibiting significantly different overall survival (OS) and progression-free survival (PFS), with the low-risk group showing more favorable outcomes. The high-risk group was associated with an immunosuppressive microenvironment, higher tumor mutation burden (TMB), and increased sensitivity to certain chemotherapeutic drugs (e.g., Sorafenib). Finally, RT-qPCR validation revealed that all nine lncRNAs were significantly upregulated in HCC tissues.

Conclusion: The nine-lncRNA signature exhibits robust predictive power for HCC prognosis and provides novel insights into the mechanisms of lncRNA-regulated palmitoylation in HCC development.

The prolonged and intricate history of oncological treatments has transitioned significantly since the introduction of chemotherapy. Substantial therapeutic benefits in cancer therapy have been achieved by the integration of conventional treatments with molecular biosciences and omics technologies. Human epidermal growth factor receptor, hormone receptors, and angiogenesis factors are among the established therapies in tumor reduction and managing side effects. Novel targeted therapies like KRAS G12C, Claudin-18 isoform 2 (CLDN18.2), Trophoblast cell-surface antigen 2 (TROP2), and epigenetic regulators emphasize their promise in advancing precision medicine. However, in many cases, the resistance mechanisms associated with these interventions render them ineffective in carrying out their functions. The purpose of this review is to provide a comprehensive and up-to-date examination of both established and emerging drug targets and mechanisms of treatment resistance in oncology. This review seeks to elucidate recent advancements, address persisting challenges, and explore opportunities for innovative developments in cancer target research. Additionally, it explores the growing role of artificial intelligence in reshaping cancer drug discovery and development frameworks as potential avenues for future research. In conclusion, innovative approaches in oncology, supported by pharmacological research, ongoing clinical trials, molecular biosciences, and artificial intelligence, are poised to significantly transform cancer treatment.

Objectives: Immunotherapy based on immune checkpoint blockade (ICB) has become a key treatment for melanoma. However, the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance. This study aims to collect the most recent information on melanoma immunotherapy, discuss potential strategies to overcome resistance to immunotherapy, and identify areas that require further analysis.

Methods: To achieve this goal, scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed. The databases were searched using the following terms: "melanoma", "immunotherapy", "Immune Checkpoint Blockade", and "immunoresistance".

Results: The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1 (TBK-1), fecal microbiota transplant (FMT), Toll-like Receptor 9 (TLR9), lipid nanoparticles (LNPs) containing a stimulator of an interferon gene agonist (STING), BRAF inhibitors, Lymphocyte Activation Gene (LAG-3), T-Cell Immunoglobulin and ITIM Domain (TIGIT), and oncolytic viruses (OVs) as potential methods to enhance melanoma sensitivity to ICB.

Discussion: To optimize immunotherapy, further research is needed to determine the detailed mechanisms of action, safety profiles, tolerability, and precise patient selection criteria for methods capable of overcoming melanoma's immunoresistance.

Objectives: Glioblastoma (GBM) is a prevalent malignant brain tumor prone to drug resistance. We previously found a strong correlation between SH3 domain GRB2-like endophilin B1 (SH3GLB1) and superoxide dismutase 2 (SOD2), which converts O₂ to hydrogen peroxide (H₂O₂). Prior studies show that H₂O₂ redox signaling is vital for physiological processes and can drive tumor progression. Therefore, we aim to define how H₂O₂ signaling regulates SH3GLB1 and AKT (protein kinase B) pathways in GBM and to assess whether modulating H₂O₂ reverses temozolomide (TMZ) resistance.

Methods: We used cultured cells and pharmacological inhibitors and activators to confirm the significance of H₂O₂ signaling. GBM cells were used to verify the role of H₂O₂ signaling in cell state transitions and animal experiments identified optimal treatment strategies.

Results: We found that SOD2 acts as an upstream regulator of SH3GLB1. When SOD inhibitors and TMZ were combined, cells showed reduced SH3GLB1 and autophagy levels. SH3GLB1 was found to be regulated by H₂O₂ via AKT signaling using redox homeostasis-regulating experiments. Although treatment-induced changes in mitochondrial H₂O₂ levels mirrored those in the cytosol, parental and resistant cells exhibited divergent fates, highlighting cell-fate plasticity. TMZ combined with a redox modulator reduced resistant tumor cell growth (about 2/3 reduction of tumor size; p < 0.05) and suppressed SH3GLB1 and autophagy levels in animal models. The TMZ-induced increase in SH3GLB1 expression was reversed by HgCl₂, which inhibited the aquaporin-9/AKT signaling.

Conclusion: Overall, these findings underscore the importance of H₂O₂-SH3GLB1 signaling in GBM and may inform future therapeutic strategies for overcoming TMZ resistance.