Oncogenesis最新文献_第6页

Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway 有丝分裂 MTH1 抑制剂 TH1579 通过 cGAS-STING 通路诱导 PD-L1 表达和炎症反应

IF 6.2 2区医学

Oncogenesis Pub Date : 2024-05-25 DOI: 10.1038/s41389-024-00518-1

Jianyu Shen, Emilio Guillén Mancina, Shenyu Chen, Theodora Manolakou, Helge Gad, Ulrika Warpman Berglund, Kumar Sanjiv, Thomas Helleday

{"title":"Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway","authors":"Jianyu Shen, Emilio Guillén Mancina, Shenyu Chen, Theodora Manolakou, Helge Gad, Ulrika Warpman Berglund, Kumar Sanjiv, Thomas Helleday","doi":"10.1038/s41389-024-00518-1","DOIUrl":"https://doi.org/10.1038/s41389-024-00518-1","url":null,"abstract":"The mitotic MTH1 inhibitor TH1579 is a dual inhibitor that inhibits mitosis and incorporation of oxidative DNA damage and leads to cancer-specific cell death. The response to immune checkpoint inhibitor (ICI) treatment is often augmented by DNA damaging agents through the cGAS-STING pathway. This study investigates whether TH1579 can improve the efficacy of immune checkpoint blockades through its immunomodulatory properties. Various human and murine cancer cell lines were treated with mitotic MTH1i TH1579, and the expression of PD-L1 and T-cell infiltration-related chemokines was analysed by flow cytometry and real-time qPCR. Syngeneic mouse models were established to examine the combined effect of TH1579 and PD-L1 blockade. In our investigation, we found that TH1579 upregulates PD-L1 expression at both the protein and mRNA levels in human cancer cell lines. However, in murine cell lines, the increase was less pronounced. An in vivo experiment in a syngeneic mouse melanoma model showed that TH1579 treatment significantly increased the efficacy of atezolizumab, an anti-PD-L1 antibody, compared to vehicle or atezolizumab monotherapy. Furthermore, TH1579 exhibited immune-modulatory properties, elevating cytokines such as IFN-β and chemokines including CCL5 and CXCL10, in a cGAS-STING pathway-dependent manner. In conclusion, TH1579 has the potential to improve ICI treatment by modulating immune checkpoint-related proteins and pathways.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"10 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141147822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An E3 ligase TRIM1 promotes colorectal cancer progression via K63-linked ubiquitination and activation of HIF1α. E3连接酶TRIM1通过与K63连接的泛素化和激活HIF1α促进结直肠癌的进展。

IF 5.9 2区医学

Oncogenesis Pub Date : 2024-05-20 DOI: 10.1038/s41389-024-00517-2

Liuliu Shi, Xianglan Fang, Lijie Du, Jin Yang, Juan Xue, Xiaokai Yue, Duoshuang Xie, Yuanjian Hui, Kun Meng

{"title":"An E3 ligase TRIM1 promotes colorectal cancer progression via K63-linked ubiquitination and activation of HIF1α.","authors":"Liuliu Shi, Xianglan Fang, Lijie Du, Jin Yang, Juan Xue, Xiaokai Yue, Duoshuang Xie, Yuanjian Hui, Kun Meng","doi":"10.1038/s41389-024-00517-2","DOIUrl":"10.1038/s41389-024-00517-2","url":null,"abstract":"Accumulating studies have shown that E3 ligases play crucial roles in regulating cellular biological processes and signaling pathways during carcinogenesis via ubiquitination. Tripartite-motif (TRIM) ubiquitin E3 ligases consist of over 70 members. However, the clinical significance and their contributions to tumorigenesis remain largely unknown. In this study, we analyzed the RNA-sequencing expression of TRIM E3 ligases in colorectal cancer (CRC) and identified 10 differentially expressed genes, among which TRIM1 expression predicted poor prognosis of CRC patients. We demonstrated that TRIM1 expression is positively associated with CRC pathological stages, and higher expression is positively correlated with infiltrating levels of immune cells and immunotherapy biomarkers. TRIM1 expression promotes the proliferation and migration of colorectal cancer cells in vitro and in vivo. Transcriptional analysis showed that TRIM1 is responsible for metabolism promotion and immune suppression. Mechanistically, we found that TRIM1 binds HIF1α and mediates its K63-linked ubiquitination, which is required for HIF1α nuclear translocation and subsequent activation. Ubiquitination occurs at Lys214 in the loop between the two PAS domains of HIF1α, and mutation of Lys214 severely disturbs the function of HIF1α. Besides, HIF1α ubiquitination enhances its binding with proteins involved in cellular trafficking and nucleocytoplasmic transport pathway. Collectively, our results indicate TRIM1's role in predicting prognosis and reveal how TRIM1 functions to upregulate HIF1α expression and promote tumor cell proliferation.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"16"},"PeriodicalIF":5.9,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11106307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071647","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}

引用次数: 0

NAC1 transcriptional activation of LDHA induces hepatitis B virus immune evasion leading to cirrhosis and hepatocellular carcinoma development NAC1 对 LDHA 的转录激活诱导乙型肝炎病毒免疫逃避，导致肝硬化和肝细胞癌的发展

IF 6.2 2区医学

Oncogenesis Pub Date : 2024-05-04 DOI: 10.1038/s41389-024-00515-4

Wenbiao Chen, Liliangzi Guo, Huixuan Xu, Yong Dai, Jun Yao, Lisheng Wang

{"title":"NAC1 transcriptional activation of LDHA induces hepatitis B virus immune evasion leading to cirrhosis and hepatocellular carcinoma development","authors":"Wenbiao Chen, Liliangzi Guo, Huixuan Xu, Yong Dai, Jun Yao, Lisheng Wang","doi":"10.1038/s41389-024-00515-4","DOIUrl":"https://doi.org/10.1038/s41389-024-00515-4","url":null,"abstract":"Our study aimed to elucidate the molecular mechanisms underlying NAC1 (nucleus accumbens associated 1) transcriptional regulation of LDHA and its role in HBV immune evasion, thus contributing to the development of cirrhosis and hepatocellular carcinoma (HCC). Utilizing public datasets, we performed differential gene expression and weighted gene co-expression network analysis (WGCNA) on HBV-induced cirrhosis/HCC data. We identified candidate genes by intersecting differentially expressed genes with co-expression modules. We validated these genes using the TCGA database, conducting survival analysis to pinpoint key genes affecting HBV-HCC prognosis. We also employed the TIMER database for immune cell infiltration data and analyzed correlations with identified key genes to uncover potential immune escape pathways. In vitro, we investigated the impact of NAC1 and LDHA on immune cell apoptosis and HBV immune evasion. In vivo, we confirmed these findings using an HBV-induced cirrhosis model. Bioinformatics analysis revealed 676 genes influenced by HBV infection, with 475 genes showing differential expression in HBV-HCC. NAC1 emerged as a key gene, potentially mediating HBV immune escape through LDHA transcriptional regulation. Experimental data demonstrated that NAC1 transcriptionally activates LDHA, promoting immune cell apoptosis and HBV immune evasion. Animal studies confirmed these findings, linking NAC1-mediated LDHA activation to cirrhosis and HCC development. NAC1, highly expressed in HBV-infected liver cells, likely drives HBV immune escape by activating LDHA expression, inhibiting CD8 + T cells, and promoting cirrhosis and HCC development.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"2019 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140826988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Phenotyping of cancer-associated somatic mutations in the BCL2 transmembrane domain BCL2跨膜结构域癌症相关体细胞突变的表型分析

IF 6.2 2区医学

Oncogenesis Pub Date : 2024-04-26 DOI: 10.1038/s41389-024-00516-3

Diego Leiva, Estefanía Lucendo, Alicia Belén García-Jareño, Mónica Sancho, Mar Orzáez

{"title":"Phenotyping of cancer-associated somatic mutations in the BCL2 transmembrane domain","authors":"Diego Leiva, Estefanía Lucendo, Alicia Belén García-Jareño, Mónica Sancho, Mar Orzáez","doi":"10.1038/s41389-024-00516-3","DOIUrl":"https://doi.org/10.1038/s41389-024-00516-3","url":null,"abstract":"The BCL2 family of proteins controls cell death by modulating the permeabilization of the mitochondrial outer membrane through a fine-tuned equilibrium of interactions among anti- and pro-apoptotic members. The upregulation of anti-apoptotic BCL2 proteins represents an unfavorable prognostic factor in many tumor types due to their ability to shift the equilibrium toward cancer cell survival. Furthermore, cancer-associated somatic mutations in BCL2 genes interfere with the protein interaction network, thereby promoting cell survival. A range of studies have documented how these mutations affect the interactions between the cytosolic domains of BCL2 and evaluate the impact on cell death; however, as the BCL2 transmembrane interaction network remains poorly understood, somatic mutations affecting transmembrane regions have been classified as pathogenic-based solely on prediction algorithms. We comprehensively investigated cancer-associated somatic mutations affecting the transmembrane domain of BCL2 proteins and elucidated their effect on membrane insertion, hetero-interactions with the pro-apoptotic protein BAX, and modulation of cell death in cancer cells. Our findings reveal how specific mutations disrupt switchable interactions, alter the modulation of apoptosis, and contribute to cancer cell survival. These results provide experimental evidence to distinguish BCL2 transmembrane driver mutations from passenger mutations and provide new insight regarding selecting precision anti-tumor treatments.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"56 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140803172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Acidovorax temperans skews neutrophil maturation and polarizes Th17 cells to promote lung adenocarcinoma development 嗜酸性粒细胞扭曲了中性粒细胞的成熟并使Th17细胞极化，从而促进了肺腺癌的发展

IF 6.2 2区医学

Oncogenesis Pub Date : 2024-04-03 DOI: 10.1038/s41389-024-00513-6

Joshua K. Stone, Natalia von Muhlinen, Chenran Zhang, Ana I. Robles, Amy L. Flis, Eleazar Vega-Valle, Akihiko Miyanaga, Masaru Matsumoto, K. Leigh Greathouse, Tomer Cooks, Giorgio Trinchieri, Curtis C. Harris

{"title":"Acidovorax temperans skews neutrophil maturation and polarizes Th17 cells to promote lung adenocarcinoma development","authors":"Joshua K. Stone, Natalia von Muhlinen, Chenran Zhang, Ana I. Robles, Amy L. Flis, Eleazar Vega-Valle, Akihiko Miyanaga, Masaru Matsumoto, K. Leigh Greathouse, Tomer Cooks, Giorgio Trinchieri, Curtis C. Harris","doi":"10.1038/s41389-024-00513-6","DOIUrl":"https://doi.org/10.1038/s41389-024-00513-6","url":null,"abstract":"Change within the intratumoral microbiome is a common feature in lung and other cancers and may influence inflammation and immunity in the tumor microenvironment, affecting growth and metastases. We previously characterized the lung cancer microbiome in patients and identified Acidovorax temperans as enriched in tumors. Here, we instilled A. temperans in an animal model driven by mutant K-ras and Tp53. This revealed A. temperans accelerates tumor development and burden through infiltration of proinflammatory cells. Neutrophils exposed to A. temperans displayed a mature, pro-tumorigenic phenotype with increased cytokine signaling, with a global shift away from IL-1β signaling. Neutrophil to monocyte and macrophage signaling upregulated MHC II to activate CD4+ T cells, polarizing them to an IL-17A+ phenotype detectable in CD4+ and γδ populations (T17). These T17 cells shared a common gene expression program predictive of poor survival in human LUAD. These data indicate bacterial exposure promotes tumor growth by modulating inflammation.<figure></figure>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"53 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140600136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RIOK3 sustains colorectal cancer cell survival under glucose deprivation via an HSP90α-dependent pathway RIOK3 通过 HSP90α 依赖性途径维持葡萄糖剥夺条件下结直肠癌细胞的存活

IF 6.2 2区医学

Oncogenesis Pub Date : 2024-03-07 DOI: 10.1038/s41389-024-00514-5

Nan Zhang, Lu Dong, Tingting Ning, Feng Du, Mengran Zhao, Junxuan Xu, Sian Xie, Si Liu, Xiujing Sun, Peng Li, Shutian Zhang, Shengtao Zhu

{"title":"RIOK3 sustains colorectal cancer cell survival under glucose deprivation via an HSP90α-dependent pathway","authors":"Nan Zhang, Lu Dong, Tingting Ning, Feng Du, Mengran Zhao, Junxuan Xu, Sian Xie, Si Liu, Xiujing Sun, Peng Li, Shutian Zhang, Shengtao Zhu","doi":"10.1038/s41389-024-00514-5","DOIUrl":"https://doi.org/10.1038/s41389-024-00514-5","url":null,"abstract":"Glucose oxidation via the pentose phosphate pathway serves as the primary cellular mechanism for generating nicotinamide adenine dinucleotide phosphate (NADPH). The central regions of solid tumors typically experience glucose deficiency, emphasizing the need for sustained NADPH production crucial to tumor cell survival. This study highlights the crucial role of RIOK3 in maintaining NADPH production and colorectal cancer (CRC) cell survival during glucose deficiency. Our findings revealed upregulated RIOK3 expression upon glucose deprivation, with RIOK3 knockout significantly reducing cancer cell survival. Mechanistically, RIOK3 interacts with heat shock protein 90α (HSP90α), a chaperone integral to various cellular processes, thereby facilitating HSP90α binding to isocitrate dehydrogenase 1 (IDH1). This interaction further upregulates IDH1 expression, enhancing NADPH production and preserving redox balance. Furthermore, RIOK3 inhibition had no discernible effect on intracellular NADPH levels and cell death rates in HSP90α-knockdown cells. Collectively, our findings suggest that RIOK3 sustains colon cancer cell survival in low-glucose environments through an HSP90α-dependent pathway. This highlights the significance of the RIOK3–HSP90α–IDH1 cascade, providing insights into potential targeted therapeutic strategies for CRC in metabolic stress conditions.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"286 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140057699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Designing patient-oriented combination therapies for acute myeloid leukemia based on efficacy/toxicity integration and bipartite network modeling. 基于疗效/毒性整合和双向网络建模，设计以患者为导向的急性髓性白血病联合疗法。

IF 6.2 2区医学

Oncogenesis Pub Date : 2024-03-01 DOI: 10.1038/s41389-024-00510-9

Mehdi Mirzaie, Elham Gholizadeh, Juho J Miettinen, Filipp Ianevski, Tanja Ruokoranta, Jani Saarela, Mikko Manninen, Susanna Miettinen, Caroline A Heckman, Mohieddin Jafari

{"title":"Designing patient-oriented combination therapies for acute myeloid leukemia based on efficacy/toxicity integration and bipartite network modeling.","authors":"Mehdi Mirzaie, Elham Gholizadeh, Juho J Miettinen, Filipp Ianevski, Tanja Ruokoranta, Jani Saarela, Mikko Manninen, Susanna Miettinen, Caroline A Heckman, Mohieddin Jafari","doi":"10.1038/s41389-024-00510-9","DOIUrl":"10.1038/s41389-024-00510-9","url":null,"abstract":"Acute myeloid leukemia (AML), a heterogeneous and aggressive blood cancer, does not respond well to single-drug therapy. A combination of drugs is required to effectively treat this disease. Computational models are critical for combination therapy discovery due to the tens of thousands of two-drug combinations, even with approved drugs. While predicting synergistic drugs is the focus of current methods, few consider drug efficacy and potential toxicity, which are crucial for treatment success. To find effective new drug candidates, we constructed a bipartite network using patient-derived tumor samples and drugs. The network is based on drug-response screening and summarizes all treatment response heterogeneity as drug response weights. This bipartite network is then projected onto the drug part, resulting in the drug similarity network. Distinct drug clusters were identified using community detection methods, each targeting different biological processes and pathways as revealed by enrichment and pathway analysis of the drugs' protein targets. Four drugs with the highest efficacy and lowest toxicity from each cluster were selected and tested for drug sensitivity using cell viability assays on various samples. Results show that ruxolitinib-ulixertinib and sapanisertib-LY3009120 are the most effective combinations with the least toxicity and the best synergistic effect on blast cells. These findings lay the foundation for personalized and successful AML therapies, ultimately leading to the development of drug combinations that can be used alongside standard first-line AML treatment.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"11"},"PeriodicalIF":6.2,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10907624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140013100","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}

引用次数: 0

Progesterone receptor potentiates macropinocytosis through CDC42 in pancreatic ductal adenocarcinoma. 胰腺导管腺癌中的黄体酮受体通过 CDC42 强化大蛋白细胞增殖。

IF 6.2 2区医学

Oncogenesis Pub Date : 2024-02-29 DOI: 10.1038/s41389-024-00512-7

Ying-Na Liao, Yan-Zhi Gai, Li-Heng Qian, Hong Pan, Yi-Fan Zhang, Pin Li, Ying Guo, Shu-Xin Li, Hui-Zhen Nie

{"title":"Progesterone receptor potentiates macropinocytosis through CDC42 in pancreatic ductal adenocarcinoma.","authors":"Ying-Na Liao, Yan-Zhi Gai, Li-Heng Qian, Hong Pan, Yi-Fan Zhang, Pin Li, Ying Guo, Shu-Xin Li, Hui-Zhen Nie","doi":"10.1038/s41389-024-00512-7","DOIUrl":"10.1038/s41389-024-00512-7","url":null,"abstract":"Endocrine receptors play an essential role in tumor metabolic reprogramming and represent a promising therapeutic avenue in pancreatic ductal adenocarcinoma (PDAC). PDAC is characterized by a nutrient-deprived microenvironment. To meet their ascendant energy demands, cancer cells can internalize extracellular proteins via macropinocytosis. However, the roles of endocrine receptors in macropinocytosis are not clear. In this study, we found that progesterone receptor (PGR), a steroid-responsive nuclear receptor, is highly expressed in PDAC tissues obtained from both patients and transgenic LSL-KrasG12D/+; LSL-Trp53R172H/+; PDX1-cre (KPC) mice. Moreover, PGR knockdown restrained PDAC cell survival and tumor growth both in vitro and in vivo. Genetic and pharmacological PGR inhibition resulted in a marked attenuation of macropinocytosis in PDAC cells and subcutaneous tumor models, indicating the involvement of this receptor in macropinocytosis regulation. Mechanistically, PGR upregulated CDC42, a critical regulator in macropinocytosis, through PGR-mediated transcriptional activation. These data deepen the understanding of how the endocrine system influences tumor progression via a non-classical pathway and provide a novel therapeutic option for patients with PDAC.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"10"},"PeriodicalIF":6.2,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10904380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139997026","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}

引用次数: 0

PKC-independent PI3K signalling diminishes PKC inhibitor sensitivity in uveal melanoma 不依赖 PKC 的 PI3K 信号降低了葡萄膜黑色素瘤对 PKC 抑制剂的敏感性

IF 6.2 2区医学

Oncogenesis Pub Date : 2024-02-28 DOI: 10.1038/s41389-024-00511-8

John J. Park, Sabine Abou Hamad, Ashleigh Stewart, Matteo S. Carlino, Su Yin Lim, Helen Rizos

{"title":"PKC-independent PI3K signalling diminishes PKC inhibitor sensitivity in uveal melanoma","authors":"John J. Park, Sabine Abou Hamad, Ashleigh Stewart, Matteo S. Carlino, Su Yin Lim, Helen Rizos","doi":"10.1038/s41389-024-00511-8","DOIUrl":"https://doi.org/10.1038/s41389-024-00511-8","url":null,"abstract":"Protein kinase C (PKC) is activated downstream of gain-of-function GNAQ or GNA11 (GNAQ/GNA11) mutations in over 90% of uveal melanoma (UM). Phase I clinical trials of PKC inhibitors have shown modest response rates with no survival benefit in metastatic UM. Although PKC inhibitors actively suppress mitogen-activated protein kinase (MAPK) signalling in UM, the effect on other UM signalling cascades is not well understood. We examined the transcriptome of UM biopsies collected pre- and post-PKC inhibitor therapy and confirmed that MAPK, but not PI3K/AKT signalling, was inhibited early during treatment with the second-generation PKC inhibitor IDE196. Similarly, in GNAQ/GNA11-mutant UM cell models, PKC inhibitor monotherapy effectively suppressed MAPK activity, but PI3K/AKT signalling remained active, and thus, concurrent inhibition of PKC and PI3K/AKT signalling was required to synergistically induce cell death in a panel of GNAQ/GNA11-mutant UM cell lines. We also show that re-activation of MAPK signalling has a dominant role in regulating PKC inhibitor responses in UM and that PI3K/AKT signalling diminishes UM cell sensitivity to PKC inhibitor monotherapy. Thus, combination therapies targeting PKC and PKC-independent signalling nodes, including PI3K/AKT activity, are required to improve responses in patients with metastatic UM.<figure></figure>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"82 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139987822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DDX3X interacts with SIRT7 to promote PD-L1 expression to facilitate PDAC progression DDX3X 与 SIRT7 相互作用，促进 PD-L1 的表达，从而推动 PDAC 的进展

IF 6.2 2区医学

Oncogenesis Pub Date : 2024-02-05 DOI: 10.1038/s41389-024-00509-2

Tianming Zhao, Hanlong Zhu, Tianhui Zou, Si Zhao, Lin Zhou, Muhan Ni, Feng Liu, Hao Zhu, Xiaotan Dou, Jian Di, Bing Xu, Lei Wang, Xiaoping Zou

{"title":"DDX3X interacts with SIRT7 to promote PD-L1 expression to facilitate PDAC progression","authors":"Tianming Zhao, Hanlong Zhu, Tianhui Zou, Si Zhao, Lin Zhou, Muhan Ni, Feng Liu, Hao Zhu, Xiaotan Dou, Jian Di, Bing Xu, Lei Wang, Xiaoping Zou","doi":"10.1038/s41389-024-00509-2","DOIUrl":"https://doi.org/10.1038/s41389-024-00509-2","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3>Pancreatic ductal adenocarcinoma (PDAC) is recognized as the most aggressive and fatal malignancy. A previous study reported that PDAC patients who exhibit elevated levels of DDX3X have a poor prognosis and low overall survival rate. However, the underlying molecular mechanism remains unclear. This study aimed to investigate the specific roles of DDX3X in PDAC. Multiple bioinformatics analyses were used to evaluate DDX3X expression and its potential role in PDAC. In vitro and in vivo studies were performed to assess the effects of DDX3X on PDAC cell growth. Furthermore, Western blotting, quantitative PCR, immunohistochemistry, immunofluorescence, mass spectrometry, coimmunoprecipitation and multiplexed immunohistochemical staining were conducted to identify the specific regulatory mechanism in PDAC. The results verified that DDX3X expression is notably upregulated in the tumor tissue vs. normal tissue of PDAC patients. DDX3X knockdown markedly suppressed the proliferation, invasion and migration of PDAC cells in vitro and inhibited tumor growth in vivo. Conversely, overexpression of DDX3X induced the opposite effect. Further studies supported that the DDX3X protein can associate with sirtuin 7 (SIRT7) to stimulate PDAC carcinogenesis and progression. Furthermore, SIRT7 inhibition significantly impeded DDX3X-mediated tumor growth both ex vivo and in vivo. The results also revealed that programmed death ligand 1 (PD-L1) expression is positively correlated with DDX3X expression. These results reveal significant involvement of the DDX3X-SIRT7 axis in the initiation and advancement of PDAC and offer previously undiscovered therapeutic options for PDAC management.<figure></figure>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"731 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139688969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0