Translational Oncology最新文献

{"title":"Exogenous dihomo-γ-linolenic acid triggers ferroptosis via ACSL4-mediated lipid metabolic reprogramming in acute myeloid leukemia cells","authors":"Xiandong Jiang ,&nbsp;Yingying Huang ,&nbsp;Xiaoying Hong ,&nbsp;Wei Wu ,&nbsp;Yanfeng Lin ,&nbsp;Liping Lin ,&nbsp;Yan Xue ,&nbsp;Donghong Lin","doi":"10.1016/j.tranon.2024.102227","DOIUrl":"10.1016/j.tranon.2024.102227","url":null,"abstract":"<div><div>Ferroptosis is a novel type of programmed cell death caused by excessive iron-dependent lipid peroxidation. According to various studies, there may be a link between ferroptosis and lipid metabolism. However, few studies have been reported on the lipid metabolism of ferroptosis in acute myeloid leukemia (AML). Here, we analyzed the relationship between lipid metabolism and ferroptosis in AML cells to explore new clinical treatment strategies. This study found that 12 fatty acids were significantly changed in acute myeloid leukemia cell ferroptosis, including dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), docosahexaenoic acid (DHA), etc. Exogenous DGLA substantially increases the sensitivity to ferroptosis and induces ferroptosis alone in AML cells. In addition, acyl-CoA synthetase long-chain family member 4 (ACSL4) knockout significantly inhibited DGLA-induced AML cells ferroptosis, and ACSL4 regulates DGLA-associated lipid synthesis to affect the sensitivity of AML cells to ferroptosis. Collectively, our studies indicate that a DGLA-enriched diet significantly restricted the growth of leukemia cells as well as induced ferroptosis in vivo.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102227"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UGCG promotes chemoresistance and breast cancer progression via NF-κB and Wnt/β-catenin pathway activation","authors":"Li Long ,&nbsp;Lei Wang ,&nbsp;Yiran Liang ,&nbsp;Fangzhou Ye ,&nbsp;Yuhan Jin ,&nbsp;Dan Luo ,&nbsp;Xiaoyan Li ,&nbsp;Yajie Wang ,&nbsp;Yaming Li ,&nbsp;Dianwen Han ,&nbsp;Bing Chen ,&nbsp;Wenjing Zhao ,&nbsp;Lijuan Wang ,&nbsp;Qifeng Yang","doi":"10.1016/j.tranon.2024.102241","DOIUrl":"10.1016/j.tranon.2024.102241","url":null,"abstract":"<div><h3>Background</h3><div>Taxane-based chemotherapy is the primary treatment for triple-negative breast cancer (TNBC), yet clinical outcomes remain unsatisfactory due to the persistence of chemoresistance. Identifying key factors that contribute to chemoresistance and understanding the associated molecular mechanisms is therefore essential.</div></div><div><h3>Method</h3><div>The GEO databases were utilized to pinpoint factors related to chemoresistance, which were subsequently validated using clinical tissue samples. The role of UGCG in the malignant progression and chemoresistance of TNBC was assessed through various functional assays. Western blotting, qRT-PCR, and immunohistochemistry were employed to investigate the signaling pathways associated with UGCG in TNBC.</div></div><div><h3>Results</h3><div>UGCG expression was notably elevated in chemoresistant breast cancer tissues and cells, as identified in GEO databases and confirmed through immunohistochemistry. Additionally, findings from our cohorts indicated that higher levels of UGCG expression correlated with a lower rate of pathological complete response (pCR), suggesting it could serve as an independent predictor of chemotherapy effectiveness. Gain- and loss-of-function experiments demonstrated that UGCG enhanced the proliferation, metastasis, and stemness of breast cancer cells. Furthermore, treatment with paclitaxel or docetaxel resulted in increased UGCG expression, which in turn reduced chemotherapy-induced cell apoptosis and improved drug resistance and metastatic capabilities. Mechanistically, UGCG was found to amplify the activation of NF-κB and Wnt/β-catenin pathways, and the use of inhibitors targeting these pathways diminished the UGCG-induced malignant effects.</div></div><div><h3>Conclusion</h3><div>Our findings underscore the significant role of UGCG in the chemoresistance and progression of breast cancer, suggesting it as a predictive biomarker and potential therapeutic target to combat chemoresistance in this disease.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102241"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11700287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic implications of immune classification based on PD-L1 expression and tumor-infiltrating lymphocytes in endocervical adenocarcinoma","authors":"Li-Jun Wei ,&nbsp;Zi-Yun Wu ,&nbsp;Li-Yan Wu ,&nbsp;Ying-Wen Wu ,&nbsp;Hao-Yu Liang ,&nbsp;Rong-Zhen Luo ,&nbsp;Li-Li Liu","doi":"10.1016/j.tranon.2024.102265","DOIUrl":"10.1016/j.tranon.2024.102265","url":null,"abstract":"<div><h3>Background</h3><div>Endocervical adenocarcinoma (ECA) comprises a heterogeneous group of diseases whose incidence has increased significantly in recent decades. ECA can be histologically classified into human papillomavirus-associated (HPVA) and non-HPVA (NHPVA) types. Given the variability in pathological features and clinical behavior between the subtypes, evaluating their respective immune microenvironments is essential. They can be categorized into distinct tumor microenvironment immune types (TMIT).</div></div><div><h3>Methods</h3><div>A total of 540 surgically resected ECA samples were classified into HPVA and NHPVA subgroups. Tumor-infiltrating immune markers were assessed using immunohistochemistry. We categorized ECA into four TMIT based on PD-L1 and CD8+ tumor-infiltrating lymphocytes (TILs) expression, and analyzed their prognostic significance.</div></div><div><h3>Results</h3><div>PD-L1 positivity was observed in 319 out of 464 (68.8%) HPVA and 55 out of 76 (72.4%) NHPVA. Across the entire cohort, high CD8+ TILs expression was significantly associated with improved disease-free survival (DFS, <em>p</em>=0.018) and overall survival (OS, <em>p</em>=0.031). A total of 177 samples (32.8%) were classified as TMIT I (high PD-L1 and high CD8+ TILs), exhibiting markedly denser immune cell infiltration compared to the other TMIT groups. In NHPVA subgroup, TMIT was significantly associated with both DFS (<em>p</em>=0.005) and OS (<em>p</em>=0.003). Multivariate analysis identified TMIT as an independent prognostic factor for DFS in the NHPVA group, with TMIT I indicating a more favorable prognosis (<em>p</em>=0.042).</div></div><div><h3>Conclusions</h3><div>TMIT I group within the NHPVA population is most likely to benefit from PD-L1/PD-1 blockade immunotherapies. The immune classification of ECA demonstrates significant prognostic value, suggesting its potential utility in guiding clinical stratification and therapeutic decision-making.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102265"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11750284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Composition analysis and mechanism of Guizhi Fuling capsule in anti-cisplatin-resistant ovarian cancer","authors":"Lei Dou ,&nbsp;Yan Yan ,&nbsp;Enting Lu ,&nbsp;Fangmei Li ,&nbsp;Dongli Tian ,&nbsp;Lei Deng ,&nbsp;Xue Zhang ,&nbsp;Rongjin Zhang ,&nbsp;Yin Li ,&nbsp;Yi Zhang ,&nbsp;Ye Sun","doi":"10.1016/j.tranon.2024.102244","DOIUrl":"10.1016/j.tranon.2024.102244","url":null,"abstract":"<div><div>Objective: Cisplatin is the main chemotherapy drug for advanced ovarian cancer, but drug resistance often occurs. The aim of this study is to explore the molecular mechanism by which Guizhi Fuling capsule inhibits cisplatin resistance in ovarian cancer. Methods: First, differences in cisplatin resistance, PA2G4 gene expression, migration, and invasion in A2780 cells and A2780/DDP cells were analyzed by qRT-PCR, scratch assay, transwell, immunofluorescence, and western blotting. Then, LC-MS/MS analysis of GFC chemical composition. qRT-PCR, scratch tests, transwell, pseudopodium formation, immunofluorescence, and western blotting were used to explore the mechanism by which GFC inhibited A2780/DDP cell migration and invasion. Finally, the anti-tumor efficacy of GFC was verified by in vivo experiments. Results: A2780/DDP cells had a greater ability to migrate and invade compared to their parents. Cell viability experiments showed that the migration and invasion ability of A278/DDP cells were significantly inhibited with the increase of GFC concentration. qRT-PCR results showed that compared with the blank control group, cisplatin group and GFC group, the transcription level of PA2G4 gene in the combination treatment group was significantly reduced. We also found that GFC combined with cisplatin inhibited the PI3K/AKT/GSK-3β signaling pathway by targeting PA2G4 gene expression, inhibited the epithelial-mesenchymal transition signaling pathway, decreased cell adhesion and inhibited the formation of cell pseudopodias. Conclusion: GFC combined with cisplatin can target PA2G4 gene to regulate PI3K/AKT/GSK-3β Signaling pathway, inhibiting the invasion and migration of cisplatin resistant A2780/DDP cells in ovarian cancer.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102244"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11683237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early onset pancreatic cancer: A review","authors":"Dong Luo ,&nbsp;Yixiong Li ,&nbsp;Xiao Yu ,&nbsp;Liandong Ji ,&nbsp;Xuejun Gong","doi":"10.1016/j.tranon.2024.102239","DOIUrl":"10.1016/j.tranon.2024.102239","url":null,"abstract":"<div><div>Early-onset pancreatic cancer (EOPC) is usually defined as patients with pancreatic cancer before the age of 50 years, which is relatively rare. However, the research on EOPC is somewhat obscure, and the specific clinical and molecular characteristics of this condition are debated. In this review, we discussed the differences between EOPC and late-onset pancreatic cancer (LOPC) or average-onset pancreatic cancer (AOPC) with a focus on clinical and molecular characteristics, survival outcomes and treatment to promote the diagnosis and treatment of EOPC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102239"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical characteristics of EGFR-ctDNA shedders in EGFR-mutant NSCLC patients","authors":"Martina Ruglioni ,&nbsp;Iacopo Petrini ,&nbsp;Stefania Crucitta ,&nbsp;Andrea Sbrana ,&nbsp;Giovanna Irene Luculli ,&nbsp;Leila Sadeghi Gol ,&nbsp;Carola Forte ,&nbsp;Antonio Chella ,&nbsp;Christian Rolfo ,&nbsp;Romano Danesi ,&nbsp;Marzia Del Re","doi":"10.1016/j.tranon.2024.102228","DOIUrl":"10.1016/j.tranon.2024.102228","url":null,"abstract":"<div><h3>Background</h3><div>Circulating tumor DNA (ctDNA) revolutionized the molecular diagnostics of lung cancer by enabling non-invasive, sensitive identification of actionable mutations. However, ctDNA analysis may be challenging due to tumor shedding variability, leading to false negative results. This study aims to understand the determinants for ctDNA shedding based on clinical characteristics of lung cancer patients, for a better interpretation of false negative results to be considered when ordering ctDNA analysis for clinical practice.</div></div><div><h3>Methods</h3><div>Blood samples were collected from patients with stage IV EGFR-mutated (mEGFR) NSCLC before treatment and monitored until disease progression. EGFR was assessed on tissue by standard procedures, while EGFR status on ctDNA was tested using dPCR at baseline and at the first reassessment. NGS was used to evaluate patients mutational status at the progression of the disease.</div></div><div><h3>Results</h3><div>A total of 40 mEGFR tissue samples were collected. Plasma samples were analyzed for mEGFR before starting the first line, 65 % of patients had detectable mEGFR in ctDNA (“shedders”). Higher ECOG PS (<em>p</em> = 0.04), bilateral localization of primary tumor (<em>p</em> = 0.04), and the presence of intrathoracic/extrathoracic disease (<em>p</em> = 0.05), were associated to mEGFR shedding. Shedders had shorter PFS compared to non-shedders (<em>p</em> = 0.03). Patients with detectable mEGFR in ctDNA at the first radiological assessment exhibited worse PFS compared to patients with ctDNA clearance (<em>p</em> = 0.05).</div></div><div><h3>Conclusion</h3><div>Our preliminary data demonstrate that specific clinical characteristics predict mEGFR shedding in ctDNA of NSCLC, suggesting a potential clinical applicability for understanding potential false negative results and appropriate reporting in clinical practice.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102228"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adenomas from individuals with pathogenic biallelic variants in the MUTYH and NTHL1 genes demonstrate base excision repair tumour mutational signature profiles similar to colorectal cancers, expanding potential diagnostic and variant classification applications","authors":"Romy Walker ,&nbsp;Jihoon E. Joo ,&nbsp;Khalid Mahmood ,&nbsp;Mark Clendenning ,&nbsp;Julia Como ,&nbsp;Susan G. Preston ,&nbsp;Sharelle Joseland ,&nbsp;Bernard J. Pope ,&nbsp;Ana B.D. Medeiros ,&nbsp;Brenely V. Murillo ,&nbsp;Nicholas Pachter ,&nbsp;Kevin Sweet ,&nbsp;Allan D. Spigelman ,&nbsp;Alexandra Groves ,&nbsp;Margaret Gleeson ,&nbsp;Krzysztof Bernatowicz ,&nbsp;Nicola Poplawski ,&nbsp;Lesley Andrews ,&nbsp;Emma Healey ,&nbsp;Steven Gallinger ,&nbsp;Peter Georgeson","doi":"10.1016/j.tranon.2024.102266","DOIUrl":"10.1016/j.tranon.2024.102266","url":null,"abstract":"<div><h3>Background</h3><div>Colorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in <em>MUTYH</em> or <em>NTHL1</em> exhibit specific single base substitution (SBS) mutational signatures, namely combined SBS18 and SBS36 (SBS18+SBS36), and SBS30, respectively. The aim was to determine if adenomas from biallelic cases demonstrated these mutational signatures at diagnostic levels.</div></div><div><h3>Methods</h3><div>Whole-exome sequencing of FFPE tissue and matched blood-derived DNA was performed on 9 adenomas and 15 CRCs from 13 biallelic <em>MUTYH</em> cases, on 7 adenomas and 2 CRCs from 5 biallelic <em>NTHL1</em> cases and on 27 adenomas and 26 CRCs from 46 non-hereditary (sporadic) participants. All samples were assessed for COSMIC v3.2 SBS mutational signatures.</div></div><div><h3>Results</h3><div>In biallelic <em>MUTYH</em> cases, SBS18+SBS36 signature proportions in adenomas (mean±standard deviation, 65.6 %±29.6 %) were not significantly different to those observed in CRCs (76.2 % ± 20.5 %, <em>p-value</em>=0.37), but were significantly higher compared with non-hereditary adenomas (7.6 % ± 7.0 %, <em>p-value</em>=3.4 × 10^–4). Similarly, in biallelic <em>NTHL1</em> cases, SBS30 signature proportions in adenomas (74.5 %±9.4 %) were similar to those in CRCs (78.8 % ± 2.4 %) but significantly higher compared with non-hereditary adenomas (2.8 % ± 3.6 %, <em>p-value</em>=5.1 × 10^–7). Additionally, a compound heterozygote with the c.1187G&gt;<em>A</em> p.(Gly396Asp) pathogenic variant and the c.533G&gt;C p.(Gly178Ala) variant of unknown significance (VUS) in <em>MUTYH</em> demonstrated high levels of SBS18+SBS36 in four adenomas and one CRC, providing evidence for reclassification of the VUS to pathogenic.</div></div><div><h3>Conclusions</h3><div>SBS18+SBS36 and SBS30 were enriched in adenomas at comparable proportions to those observed in CRCs from biallelic <em>MUTYH</em> and biallelic <em>NTHL1</em> cases, respectively. Therefore, testing adenomas may improve the identification of biallelic cases and facilitate variant classification, ultimately enabling opportunities for CRC prevention.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102266"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11774829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of radiotherapy on secondary lung cancer risk and survival in elderly female breast cancer survivors","authors":"Jieming Lu ,&nbsp;Zhimin Shen ,&nbsp;Xiaoqing Wang ,&nbsp;Yanhong Lin ,&nbsp;Ziyang Han ,&nbsp;Mingqiang Kang","doi":"10.1016/j.tranon.2025.102277","DOIUrl":"10.1016/j.tranon.2025.102277","url":null,"abstract":"<div><div>This retrospective cohort study using SEER data from 2000 to 2020 examines the impact of radiotherapy on the risk of Secondary Primary Lung Cancer (SPLC) in 224,396 elderly female breast cancer survivors. Patients treated with radiotherapy displayed a 31 % increased SPLC risk compared to those not treated. Utilizing Cox Proportional Hazards and Poisson regression models, the study assessed various factors including age, race, and tumor characteristics. Propensity Score Matching (PSM) was employed to balance cohorts for survival analysis, which revealed that radiotherapy did not negatively impact overall survival despite the increased risk of SPLC. A nomogram was developed to aid clinical decision-making by predicting survival outcomes. The findings advocate for personalized treatment strategies and continuous monitoring to manage potential long-term adverse effects effectively, highlighting the need for a balanced approach in the treatment of breast cancer survivors.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102277"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of 3-mercaptopyruvate sulfurtransferase in cancer: Molecular mechanisms and therapeutic perspectives","authors":"Ka Zhang ,&nbsp;Yi-Wen Zhu ,&nbsp;Ao-Qi Tang ,&nbsp;Ze-Tao Zhou ,&nbsp;Yi-Lun Yang ,&nbsp;Zi-Hui Liu ,&nbsp;Yan Li ,&nbsp;Xiao-Yi Liang ,&nbsp;Zhi-Fen Feng ,&nbsp;Jun Wang ,&nbsp;Tong Jiang ,&nbsp;Qi-Ying Jiang ,&nbsp;Dong-Dong Wu","doi":"10.1016/j.tranon.2025.102272","DOIUrl":"10.1016/j.tranon.2025.102272","url":null,"abstract":"<div><div>The occurrence and development of tumor is mediated by a wide range of complex mechanisms. Subsequent to nitric oxide and carbon monoxide, hydrogen sulfide (H₂S) holds the distinction of being the third identified gasotransmitter. Alternation of H₂S level has been widely demonstrated to induce an array of disturbances in important cancer cell signaling pathways. As a result, the effects of H₂S-catalyzing enzymes in cancers also attract widspread attention. 3-mercaptopyruvate sulfurtransferase (3-MST) is privileged to be one of them. In fact, 3-MST is overexpressed in many tumors including human colon cancer, lung adenocarcinoma, and bladder urothelial carcinoma. But it is also lowly expressed in hepatocellular carcinoma. In this review, we focus on the generation of endogenous H₂S and polysulfides, facilitated by 3-MST. Additionally, we delve deeply into the potential role of 3-MST in tumorigenesis and development. The impact of 3-MST inhibition on the development of tumors and its potential for tumor therapy are also highlighted.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102272"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDK4/6 inhibitors promote PARP1 degradation and synergize with PARP inhibitors in non-small cell lung cancer","authors":"Carlos M Roggero ,&nbsp;Anwesha B Ghosh ,&nbsp;Anvita Devineni ,&nbsp;Shihong Ma ,&nbsp;Eliot Blatt ,&nbsp;Ganesh V. Raj ,&nbsp;Yi Yin","doi":"10.1016/j.tranon.2024.102231","DOIUrl":"10.1016/j.tranon.2024.102231","url":null,"abstract":"<div><div>Despite widespread deregulation of CDK4/6 activity in non-small cell lung cancer (NSCLC), clinical trials with CDK4/6 inhibitor (CDK4/6i) as a monotherapy have shown poor antitumor activity. Preclinical studies indicate that CDK4/6i may collaborate by influencing DNA damage repair pathways during radiotherapy. Since PARP1 expression was also significantly upregulated in NSCLC, we analyzed the efficacy of combining PARP1 and CDK4/6 inhibition in NSCLC models. We found that CDK4/6is synergize with PARP1 inhibitors (PARPis) to inhibit the clonogenic growth of RB-proficient NSCLC models. This synergy correlates with increased accumulation of DNA damage, interrupted cell-cycle checkpoints, and enhanced apoptotic cell death. Mechanistically, we showed that CDK4/6is promote PARP1 protein degradation, which lead to decreased availability of DNA repair factors involved in homologous recombination and suppression of DNA repair competency. Furthermore, we showed that PARP trapping is engaged in this synergy. We then confirmed that combining PARPi and CDK4/6i blocked the growth of NSCLC xenografts <em>in vivo</em> and patient-derived explant models <em>ex vivo</em>. Our data reveal a previously uncharacterized impact of CDK4/6i on PARP1 levels in RB-proficient NSCLC models and the engagement of PARP trapping in the synergy between CDK4/6i and PARPi. Our findings suggest combining CDK4/6i with PARPi could be a viable therapeutic strategy for patients with RB-proficient NSCLC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102231"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11683282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}