Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis.

Cancer mortality is primarily a consequence of its metastatic spread. Here, we report that methionine sulfoxide reductase A (MSRA), which can reduce oxidized methionine residues, acts as a suppressor of pancreatic ductal adenocarcinoma (PDA) metastasis. MSRA expression is decreased in the metastatic tumors of PDA patients, whereas MSRA loss in primary PDA cells promotes migration and invasion. Chemoproteomic profiling of pancreatic organoids revealed that MSRA loss results in the selective oxidation of a methionine residue (M239) in pyruvate kinase M2 (PKM2). Moreover, M239 oxidation sustains PKM2 in an active tetrameric state to promote respiration, migration, and metastasis, whereas pharmacological activation of PKM2 increases cell migration and metastasis in vivo. These results demonstrate that methionine residues can act as reversible redox switches governing distinct signaling outcomes and that the MSRA-PKM2 axis serves as a regulatory nexus between redox biology and cancer metabolism to control tumor metastasis.

Circular RNA circSLC8A1 acts as a sponge of miR-130b/miR-494 in suppressing bladder cancer progression via regulating PTEN.

BACKGROUND: Circular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs formed by a covalently closed loop, and increasing evidence has revealed that circRNAs play crucial functions in regulating gene expression. CircSLC8A1 is a circRNA generated from the SLC8A1 gene. Currently, the role and underlying molecular mechanisms of circSLC8A1 in bladder cancer remain unknown. METHODS: The differentially expressed circRNAs were identified from RNA-sequencing data, and circSLC8A1 was determined as a new candidate circRNA. qRT-PCR was used to detect the expression of circRNAs, miRNAs and mRNAs in human tissues and cells. RNA pull-down assay and luciferase reporter assay were used to investigate the interactions between the specific circRNA, miRNA and mRNA. The effects of circSLC8A1 on bladder cancer cells were explored by transfecting with plasmids in vitro and in vivo. The expression of PTEN was detected by Western blot. The biological roles were measured by wound healing assay, transwell assay, and CCK-8 assay. RESULTS: In the present study, we found that circSLC8A1 was down-regulated in bladder cancer tissues and cell lines, and circSLC8A1 expression was associated with the pathological stage and histological grade of bladder cancer. Over-expression of circSLC8A1 inhibited cell migration, invasion and proliferation both in vitro and in vivo. Mechanistically, circSLC8A1 could directly interact with miR-130b/miR-494, and subsequently act as a miRNA sponge to regulate the expression of the miR-130b/miR-494 target gene PTEN and downstream signaling pathway, which suppressed the progression of bladder cancer. CONCLUSIONS: CircSLC8A1 acts as a tumor suppressor by a novel circSLC8A1/miR-130b, miR-494/PTEN axis, which may provide a potential biomarker and therapeutic target for the management of bladder cancer.

Diphthamide Biosynthesis 1 is a Novel Oncogene in Colorectal Cancer Cells and is Regulated by MiR-218-5p.

BACKGROUND/AIMS: This study focused on the oncogenic role of Diphthamide biosynthesis 1 (DPH1) in colorectal cancer (CRC) cells. METHODS: The expression of DPH1 was determined by quantitative RT-PCR analysis and western blotting in CRC tissues. The role of DPH1 in CRC cells was investigated via cell viability and invasion assays under the condition of DPH1 silencing or overexpression. Bioinformatics analysis and luciferase reporter analysis were used to identify the upstream microRNA which might regulate DPH1.The inverse correlation between the microRNA and DPH1 was also detected in CRC cells. RESULTS: We identified an unexpected role for DPH1 as an oncogene in CRC cells. The tumour-suppressive miR-218-5p regulates DPH1 directly and negatively. Loss of miR-218-5p drives the oncogenic role of DPH1 in CRC cells. CONCLUSION: The modulation of DPH1 by miR-218-5p may be an important regulatory axis during CRCtumourigenesis.

Access to Six- and Seven-Membered 1,7-Fused Indolines via Rh(III)-Catalyzed Redox-Neutral C7-Selective C-H Functionalization of Indolines with Alkynes and Alkenes.

We report herein a new strategy for the Rh(III)-catalyzed redox-neutral C7-selective C-H activation/annulation of indolines to rapidly access various privileged 1,7-fused indolines by utilizing an oxidizing-directing group. For example, a Rh(III)-catalyzed redox-neutral C7-selective C-H functionalization of indolines with arylalkynes is described to directly access 7-membered 1,7-fused indolines. Moreover, an unprecedented intramolecular addition of an alkenyl-Cp*Rh(III) species to a carbamoyl moiety occurred to give 1H-pyrroloquinolinones when employing alkyl alkynes. Additionally, an efficient Rh(III)-catalyzed redox-neutral C7-selective C-H activation/alkenylation/aza-Michael addition of indolines is also developed to give 6-membered 1,7-fused indolines. The advantages of these processes are as follows: (1) mild and simple reaction conditions; (2) no need for an external oxidant; (3) broad scope of substrates; and (4) valuable six- or seven-membered 1,7-fused indolines as products.

Rhodium-catalyzed direct amination of arenes with nitrosobenzenes: a new route to diarylamines.

A Rh(III) -catalyzed addition of aryl CH bonds to nitrosobenzenes, followed by cleavage of the resulting hydroxylamines in situ, has been reported. Different directing groups, such as N-based heterocycles and ketoximes, can be used in this CH amination process, providing valuable diarylamines in excellent yields. Most importantly, this process provides a new method for attaching arylamine groups to aromatic rings.

Rhodium-catalyzed directed sulfenylation of arene C-H bonds.

The rhodium-catalyzed intermolecular direct C-H thiolation of arenes with aryl and alkyl disulfides was developed for the first time to provide a convenient route to aryl thioethers. This strategy is compatible with many different directing groups and exhibits excellent functional group tolerance. More significantly, mono- or dithiolation can be selectively achieved, thus providing a straightforward way for selective preparation of aryl thioethers and dithioethers.

Divergent total synthesis of triptolide, triptonide, tripdiolide, 16-hydroxytriptolide, and their analogues.

A divergent route was developed for the formal total synthesis of triptolide, triptonide, and tripdiolide, as well as a total synthesis of 16-hydroxytriptolide and their analogues in an enantioselective form. Common advanced intermediate 5 was concisely assembled by employing an indium(III)-catalyzed cationic polycyclization reaction and a palladium-catalyzed carbonylation-lactone formation reaction as key steps. This advanced intermediate was readily converted to the above natural products by using palladium-catalyzed cross-coupling or the Claisen rearrangement reaction as key steps. Additionally, preliminary structure-cytotoxic activity relationship studies of C13 suggested that it might be a new modification site that could still retain the cytotoxicity.

Semisynthesis of triptolide analogues: effect of B-ring substituents on cytotoxic activities.

A series of B-ring modified analogues of triptolide were synthesized and tested for their cytotoxicity against two human tumor cell lines (U251 and PC-3). From the current investigation, the structure-cytotoxic activity relationships of these analogues suggested that the introduction of hydroxyl, epoxide, halogen or olefinic groups on C5 and/or C6 could still retain the cytotoxicity, albeit a little less potency, and the C7,C8-ß-epoxide group of triptolide was essential to its potent cytotoxic activity.

PANoptosis-related genes function as efficient prognostic biomarkers in colon adenocarcinoma.

Background: PANoptosis is a newly discovered cell death type, and tightly associated with immune system activities. To date, the mechanism, regulation and application of PANoptosis in tumor is largely unknown. Our aim is to explore the prognostic value of PANoptosis-related genes in colon adenocarcinoma (COAD). Methods: Analyzing data from The Cancer Genome Atlas-COAD (TCGA-COAD) involving 458 COAD cases, we concentrated on five PANoptosis pathways from the Molecular Signatures Database (MSigDB) and a comprehensive set of immune-related genes. Our approach involved identifying distinct genetic COAD subtype clusters and developing a prognostic model based on these parameters. Results: The research successfully identified two genetic subtype clusters in COAD, marked by distinct profiles in PANoptosis pathways and immune-related gene expression. A prognostic model, incorporating these findings, demonstrated significant predictive power for survival outcomes, underscoring the interplay between PANoptosis and immune responses in COAD. Conclusion: This study enhances our understanding of COAD's genetic framework, emphasizing the synergy between cell death pathways and the immune system. The development of a prognostic model based on these insights offers a promising tool for personalized treatment strategies. Future research should focus on validating and refining this model in clinical settings to optimize therapeutic interventions in COAD.

A Classical Epithelial State Drives Acute Resistance to KRAS Inhibition in Pancreatic Cancer.

Intratumoral heterogeneity in pancreatic ductal adenocarcinoma (PDAC) is characterized by a balance between basal and classical epithelial cancer cell states, with basal dominance associating with chemoresistance and a dismal prognosis. Targeting oncogenic KRAS, the primary driver of pancreatic cancer, shows early promise in clinical trials, but efficacy is limited by acquired resistance. Using genetically engineered mouse models and patient-derived xenografts, we find that basal PDAC cells are highly sensitive to KRAS inhibitors. Employing fluorescent and bioluminescent reporter systems, we longitudinally track cell-state dynamics in vivo and reveal a rapid, KRAS inhibitor-induced enrichment of the classical state. Lineage tracing uncovers that these enriched classical PDAC cells are a reservoir for disease relapse. Genetic or chemotherapy-mediated ablation of the classical cell state is synergistic with KRAS inhibition, providing a preclinical proof of concept for this therapeutic strategy. Our findings motivate combining classical state-directed therapies with KRAS inhibitors to deepen responses and counteract resistance in pancreatic cancer. Significance: KRAS inhibitors hold promise in pancreatic cancer, but responses are limited by acquired resistance. We find that a classical epithelial cancer cell state is acutely resistant to KRAS inhibition and serves as a reservoir for disease relapse. Targeting the classical state alongside KRAS inhibition deepens responses, revealing a potent therapeutic strategy. See related commentary by Marasco and Misale, p. 2018.

A new ferroptosis-related signature model including messenger RNAs and long non-coding RNAs predicts the prognosis of gastric cancer patients.

Background and Objectives: Gastric cancer (GC) is among the most malignant tumor types, which causes heavy healthy and economic burden to the people and societies all around the world. Establishment of an effective set of prognostic marker will benefit a lot to the treatment of GC patients clinically. Ferroptosis is a newly identified regulated cell death modality, with tight relevance with GC development. However, its application in the prognosis of GC has not been studied in detail. Deregulated messenger RNA (mRNA) and long non-coding RNA (lncRNA) expression profile in tumor can serve as novel prognostic marker for predicting the survival and cancer relapse in patients. Methods: We downloaded ferroptosis-related gene expression microarray data, clinicopathologic information and a list of 259 ferroptosis-related genes from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Ferroptosis database, respectively. Then, correlation analysis, univariate and multivariate Cox regression analysis were used to construct a novel prognostic model for GC. Then, we validated the model in the GEO datasets. Finally, we evaluated the differences in immune microenvironment between high- and low-risk groups. Results: We utilized the ferroptosis-related mRNA and lncRNA profile to successfully construct a prognostic model (incorporating 2 mRNAs and 15 lncRNAs) in GC. Our model, integrating diverse clinical traits and critical factors of GC, showed desirable efficacy in the prognosis of GC patients. This model also manifested effectively in validation by using external patients' data. Conclusions: Our study developed a novel ferroptosis-related signature to predict the prognosis of gastric cancer patients. The ferroptosis-related signature had a favorable predictive ability. This model may greatly boost the treatment of GC patients in clinical practice.

An effective prognostic model in colon adenocarcinoma composed of cuproptosis-related epigenetic regulators.

Background: Colorectal adenocarcinoma (COAD) is a common malignant tumor with little effective prognostic markers. Cuproptosis is a newly discovered mode of cell death that may be related to epigenetic regulators. This study aimed to explore the association between epigenetic regulators and cuproptosis, and to establish a prognostic prediction model for COAD based on epigenetic regulators associated with cuproptosis (EACs). Methods: RNA sequencing data and clinical data of 524 COAD patients were obtained from the TCGA-COAD database, cuproptosis-related genes were from the FerrDb database, and epigenetic-related genes were from databases such as GO and EpiFactors. LASSO regression analysis and other methods were used to screen out epigenetic regulators associated with cuproptosis and prognosis. The risk score of each patient was calculated and the patients were divided into high-risk group and low-risk group. Next, the survival difference, functional enrichment analyses, tumor mutation burden, chemotherapy drug sensitivity and other indicators between the two groups were compared and analyzed. Results: We found 716 epigenetic regulators closely related to cuproptosis, among which 35 genes were related to prognosis of COAD. We further screened out 7 EACs from the 35 EACs to construct a prognostic prediction model. We calculated the risk score of each patient based on these 7 genes, and divided the patients into high-risk group and low-risk group. We found that the overall survival rate and progression-free survival rate of the high-risk group were significantly lower than those of the low-risk group. This model showed good predictive ability in the training set, test set and overall data set. We also constructed a prognostic prediction model based on risk score and other clinical features, and drew the corresponding Nomogram. In addition, we found significant differences between the high-risk group and the low-risk group in tumor mutation burden, chemotherapy drug sensitivity and other clinical aspects. Conclusion: We established an effective predictive prediction model for COAD based on EACs, revealing the association between epigenetic regulators and cuproptosis in COAD. We hope that this model can not only facilitate the treatment decision of COAD patients, but also promote the research progress in the field of cuproptosis.

Identification of PTPN20 as an innate immunity-related gene in gastric cancer with Helicobacter pylori infection.

Background: Gastric cancer (GC) is among the deadliest diseases with countless incidences and deaths each year. Helicobacter pylori (Hp) is the primary type of microbe that colonizes the stomach. In recent years, increasing evidence has demonstrated that Hp infection is one of the main risk factors for GC. Elucidating the molecular mechanism of how Hp leads to GC will not only benefit the treatment of GC, but also boost the development of therapeutics for other gastric disorders caused by Hp infection. In this study, we aimed to identify innate immunity-related genes in GC and investigate their potentials as prognostic markers and therapeutic targets for Hp-related GC. Methods: Firstly, we analyzed the differentially expressed innate immunity-related genes in GC samples from the TCGA database. Then prognostic correlation analysis was carried out to explore the prognostic value of these candidate genes. By combing transcriptome data, somatic mutation data, and clinical data, co-expression analysis, functional enrichment analysis, tumor mutational burden analysis, and immune infiltration analysis were performed to reveal the pathological relevance of the candidate gene. Finally, ceRNA network was constructed to identify the genes and pathways for the regulation of the candidate gene. Results: We revealed that protein tyrosine phosphatase non-receptor type 20 (PTPN20) is a significant prognostic marker in Hp-related GC. Thus, PTPN20 levels have the potential to efficiently predict the survival of Hp-related GC patients. In addition, PTPN20 is associated with immune cell infiltration and tumor mutation burden in these GC patients. Moreover, we have also identified PTPN20-related genes, PTPN20 protein-protein interactions, and the PTPN20 ceRNA network. Conclusion: Our data suggest that PTPN20 may have critical functions in Hp-related GC. Targeting PTPN20 may be a promising way to treat Hp-related GC.

Development and validation of cuproptosis-related gene signature in the prognostic prediction of liver cancer.

Liver cancer is a generic term referring to several cancer types arising from the liver. Every year, liver cancer causes lots of deaths and other burdens to the people all over the world. Though the techniques in the diagnosis and therapy of liver cancer have undergone significant advances, the current status of treating liver cancer is not satisfactory enough. The improvement of techniques for the prognosis of liver cancer patients will be a great supplement for the treatment of liver cancer. Cuproptosis is a newly identified regulatory cell death type, which may have a close connection to liver cancer pathology. Here, we developed a prognostic model for liver cancer based on the cuproptosis-related mRNAs and lncRNAs. This model can not only effectively predict the potential survival of liver cancer patients, but also be applied to evaluate the infiltration of immune cell, tumor mutation burden, and sensitivity to anti-tumor drugs in liver cancer. In addition, this model has been successfully validated in lots of liver cancer patients' data. In summary, we wish this model can become a helpful tool for clinical use in the therapy of liver cancer.

Analysis of the correlation between non-alcoholic fatty liver disease and the risk of colorectal neoplasms.

This study aims at assessing the potential association between non-alcoholic fatty liver disease (NAFLD) and colorectal neoplasms (CRN). PubMed, Cochrane Library, and Embase were searched for cohort studies. 14 cohort studies with a total population of 38,761,773 were included for meta-analysis after selection. The results showed that NAFLD is related to an increased risk of CRN (OR = 1.23; 95% CI: 1.14-1.32; I2 = 70.7%, p < 0.001). In the subgroup analysis, NAFLD were found to be the independent risk factor of colorectal adenoma (CRA) (OR = 1.29; 95% CI = 1.15-1.45; I2 = 66.4%) and colorectal cancer (CRC) (OR = 1.13; 95% CI = 1.12-1.15; I2 = 69.4%). There is no close correlation between smoking status of NAFLD patients and CRN. Interestingly, bioinformatics analysis revealed that there were overlap of dysregulated gene sets among NAFLD, CRC, and two recently identified regulated cell death types, ferroptosis and cuproptosis, respectively. Our meta- and bioinformatics analysis shows that NAFLD increases the risk of CRN. Ferroptosis and cuproptosis may be the critical links between NAFLD and CRN, respectively. These findings here support that NAFLD is necessary to be considered as an emerging risk factor for CRN.

The p300 Inhibitor A-485 Exerts Antitumor Activity in Growth Hormone Pituitary Adenoma.

CONTEXT: Growth hormone pituitary adenoma (GHPA), a major subtype of pituitary adenoma (PA), can lead to progressive somatic disfigurement, multiple complications, and even increased mortality. The efficacy of current treatments is limited; thus, a novel pharmacological treatment is urgently needed. As a histone acetyltransferase (HAT) coactivator, p300 can regulate the transcription of several genes that are crucial for PA tumorigenesis and progression. However, the role of p300 and its catalytic inhibitor in GHPA is still unclear. OBJECTIVE: We aimed to identify the expression of p300 in GHPA and in normal pituitary glands. METHODS: The expression of p300 was detected in GHPA and normal pituitary tissues. Genetic knockdown was performed by siRNA. The efficacy of the p300 inhibitor A-485 in the cell cycle, proliferation, apoptosis, and hormone secretion was investigated by flow cytometry, ELISAs, Western blotting, and qRT-PCR. RNA sequencing, bioinformatic analysis, and subsequent validation experiments were performed to reveal the potential biological mechanism of A-485. RESULTS: High expression of p300 was found in GHPA tissues compared with normal pituitary tissues. Knockdown of p300 inhibited cell proliferation and clone formation. Treatment with A-485 suppressed cell growth and inhibited the secretion of GH in vitro and in vivo. Further mechanistic studies showed that A-485 could downregulate the expression or activity of several oncogenes, such as genes in the Pttg1, c-Myc, cAMP and PI3K/AKT/mTOR signaling pathways, which are crucial for PA tumorigenesis and progression. CONCLUSION: Our findings demonstrate that inhibition of HAT p300 by its selective inhibitor A-485 is a promising therapy for GHPA.

Total synthesis of novel D-ring-modified triptolide analogues: structure-cytotoxic activity relationship studies on the D-ring of triptolide.

The total synthesis of a trans-position butenolide analogue of triptolide 3 and the semi-synthesis of analogue 4, with a furan ring, and compound 5, without a planar D-ring, are described. Studies into the antitumor activity of these compounds suggest that the five-membered unsaturated lactone ring (D-ring) of triptolide is essential to its potent anticancer activity and the C18 carbonyl group may exert an important influence on the interaction between triptolide and the target molecule(s) responsible for initiating their cytotoxic effects.

Rhodium-Catalyzed Twofold Unsymmetrical C-H Alkenylation-Annulation/Thiolation Reaction To Access Thiobenzofurans.

A Rh(III)-catalyzed twofold unsymmetrical C-H alkenylation-annulation/thiolation reaction has been developed, enabling the straightforward and efficient synthesis of various thiobenzofurans in one step. This robust protocol proceeds with a broad substrate scope and good functional group tolerance under relatively mild reaction conditions.

Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders.

SHP2, a non-receptor tyrosine phosphatase, plays a pivotal role in numerous oncogenic cell-signaling cascades like RAS-ERK, PI3K-AKT and JAK-STAT. On the other hand, proteolysis targeting chimera (PROTAC) has emerged as a promising strategy for the degradation of disease-related protein of interest (POI). SHP2 degradation via the PROTAC strategy will provide an alternative startegy for SHP2-mediated cancer therapy. Herein we described the design, synthesis and evaluation of a series of thalidomide-based heterobifunctional molecules and identified 11(ZB-S-29) as the highly efficient SHP2 degrader with a DC50 of 6.02 nM. Further mechanism investigation illustrated that 11 came into function through targeted SHP2 protein degradation.

Discovery of a subtype-selective, covalent inhibitor against palmitoylation pocket of TEAD3.

The TEA domain (TEAD) family proteins (TEAD1‒4) are essential transcription factors that control cell differentiation and organ size in the Hippo pathway. Although the sequences and structures of TEAD family proteins are highly conserved, each TEAD isoform has unique physiological and pathological functions. Therefore, the development and discovery of subtype selective inhibitors for TEAD protein will provide important chemical probes for the TEAD-related function studies in development and diseases. Here, we identified a novel TEAD1/3 covalent inhibitor (DC-TEADin1072) with biochemical IC50 values of 0.61 ± 0.02 and 0.58 ± 0.12 µmol/L against TEAD1 and TEAD3, respectively. Further chemical optimization based on DC-TEAD in 1072 yielded a selective TEAD3 inhibitor DC-TEAD3in03 with the IC50 value of 0.16 ± 0.03 µmol/L, which shows 100-fold selectivity over other TEAD isoforms in activity-based protein profiling (ABPP) assays. In cells, DC-TEAD3in03 showed selective inhibitory effect on TEAD3 in GAL4-TEAD (1-4) reporter assays with the IC50 value of 1.15 µmol/L. When administered to zebrafish juveniles, experiments showed that DC-TEAD3in03 reduced the growth rate of zebrafish caudal fins, indicating the importance of TEAD3 activity in controlling proportional growth of vertebrate appendages.