Target For Cancer Therapy Research Articles

Elucidating the Role of Pro-renin Receptors in Pancreatic Ductal Adenocarcinoma Progression: A Novel Therapeutic Target in Cancer Therapy.

Pancreatic cancer is a highly aggressive malignancy with a very poor prognosis. The 5- year survival in these patients is very low, and most patients develop drug resistance to current therapies, so additional studies are needed to identify the potential role of new drug targets for the treatment of pancreatic cancer. Recent investigations have been performed regarding the roles of pro-renin receptors (PRR) in the initiation and development of cancers. PRR is a component of the local renin-angiotensin system (RAS). Local tissue RAS has been known in diverse organ systems, including the pancreas. Various investigations have implicated that PRRs are associated with the upregulation of various signaling pathways, like the renin-angiotensin system pathway, PI3K/Akt/mTOR, and the Wnt-signaling pathways, to contribute to pathological conditions, including cancer. In this review, we presented an overview of the role of PRR in the progression of pancreatic adenocarcinoma.

Preparation and anticancer activity of telomerase inhibitor TAT-LPTS39 polypeptide.

Telomerase is activated in most cancer cells, and thus telomerase is an ideal target for cancer therapy. The human liver-associated candidate tumour suppressor LPTS/PinX1, is the only human protein reported to bind with the telomerase catalytic subunit telomerase reverse transcriptase (TERT) and inhibit telomerase activity. The C-terminal fragment of LPTS/PinX1 (LPTS/PinX1290-328) contains a telomerase inhibitory domain that is needed for inhibition of telomere elongation and induction of apoptosis. This study prepared the TAT-LPTS39 (TAT-LPTS/PinX1290-328) polypeptide and analysed its effect of the tumour growth. LPTS/PinX1290-328 was fused with TAT [11 amino acid (aa) peptide of the HIV transactivator of transcription protein] to generate the recombinant protein GST-TAT-LPTS39 and was transduced into cells. Telomerase activity was identified by the telomeric repeat amplification protocol (TRAP) and the relative telomere length (RTL) was measured by quantitative real-time polymerase chain reaction (qPCR). The effects of the TAT-LPTS39 protein on cell growth and death were evaluated by 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT), cell culture doubling time and flow cytometry assays. The cell derived xenograft (CDX) model was used to examine tumour growth inhibition effect of TAT-LPTS39 polypeptide in vivo. We successfully expressed and purified the recombinant protein GST-TAT-LPTS39 in vitro. The GST-TAT-LPTS39 protein was efficiently delivered into cells, inhibited telomerase activity and the growth of the telomerase-positive liver cancer cells BEL-7404 and QGY7701, and induced the senescence and apoptosis in telomerase-positive Hela, BEL-7404 and QGY7701 cells, but was ineffective to telomerase-negative cells in vitro. The TAT-LPTS39 polypeptide without the GST tag similarly inhibited the growth of telomerase-positive cancer cells Hela and PLC-PRF-5 in vitro, BEL-7404 CDX tumour in vivo and shortened telomere length. The TAT-LPTS39 polypeptide has the ability to inhibit telomerase activity and suppress the growth of all tested human telomerase-positive cancer cells in vitro and in vivo, suggesting a potential anticancer drug development.

Melatonin effect on breast and ovarian cancers by targeting the PI3K/Akt/mTOR pathway.

Melatonin, the hormone of the pineal gland, possesses a range of physiological functions, and recently, its anticancer effect has become more apparent. A more thorough understanding of molecular alterations in the components of several signaling pathways as new targets for cancer therapy is needed because of current innate restrictions such as drug toxicity, side effects, and acquired or de novo resistance. The PI3K/Akt/mTOR pathway is overactivated in many solid tumors, such as breast and ovarian cancers. This pathway in normal cells is essential for growth, proliferation, and survival. However, it is an undesirable characteristic in malignant cells. We have reviewed multiple studies about the effect of melatonin on breast and ovarian cancer, focusing on the PI3K/Akt/mTOR pathway. Melatonin exerts its inhibitory effects via several mechanisms. A: Downregulation of downstream or upstream components of the signaling pathway such as phosphatase and tensin homolog (PTEN), phosphatidylinositol (3,4,5)-trisphosphate kinase (PI3K), p-PI3K, Akt, p-Akt, mammalian target of rapamycin (mTOR), and mTOR complex1 (mTORC1). B: Apoptosis induction by decreasing MDM2 expression, a downstream target of Akt, and mTOR, which leads to Bad activation in addition to Bcl-XL and p53 inhibition. C: Induction of autophagy in cancer cells via activating ULK1 after mTOR inhibition, resulting in Beclin-1 phosphorylation. Beclin-1 with AMBRA1 and VPS34 promotes PI3K complex I activity and autophagy in cancer cells. The PI3K/Akt/mTOR pathway overlaps with other intracellular signaling pathways and components such as AMP-activated protein kinase (AMPK), Wnt/β-catenin, mitogen-activated protein kinase (MAPK), and other similar pathways. Cancer therapy can benefit from understanding how these pathways interact and how melatonin affects these pathways.

Computational pipeline predicting cell death suppressors as targets for cancer therapy

Identification of promising targets for cancer therapy is a global effort in precision medicine. Here, we describe a computational pipeline integrating transcriptomic and vulnerability responses to cell-death inducing drugs, to predict cell-death suppressors as candidate targets for cancer therapy. The prediction is based on two modules; the transcriptomic similarity module to identify genes whose targeting results in similar transcriptomic responses of the death-inducing drugs, and the correlation module to identify candidate genes whose expression correlates to the vulnerability of cancer cells to the same death-inducers. The combined predictors of these two modules were integrated into a single metric. As a proof-of-concept, we selected ferroptosis inducers as death-inducing drugs in triple negative breast cancer. The pipeline reliably predicted candidate genes as ferroptosis suppressors, as validated by computational methods and cellular assays. The described pipeline might be used to identify repressors of various cell-death pathways as potential therapeutic targets for different cancer types.

Beyond mitochondrial transfer, cell fusion rescues metabolic dysfunction and boosts malignancy in adenoid cystic carcinoma

Cancer cells with mitochondrial dysfunction can be rescued by cells in the tumor microenvironment. Using human adenoid cystic carcinoma cell lines and fibroblasts, we find that mitochondrial transfer occurs not only between human cells but also between human and mouse cells both invitro and invivo. Intriguingly, spontaneous cell fusion between cancer cells and fibroblasts could also emerge; specific chromosome loss might be essential for nucleus reorganization and the post-hybrid selection process. Both mitochondrial transfer through tunneling nanotubes (TNTs) and cell fusion "selectively" revive cancer cells, with mitochondrial dysfunction as a key motivator. Beyond mitochondrial transfer, cell fusion significantly enhances cancer malignancy and promotes epithelial-mesenchymal transition. Mechanistically, mitochondrial dysfunction in cancer cells causes L-lactate secretion to attract fibroblasts to extend TNTs and TMEM16F-mediated phosphatidylserine externalization, facilitating TNT formation and cell-membrane fusion. Our findings offer insights into mitochondrial transfer and cell fusion, highlighting potential cancer therapy targets.

Discovery of telomerase inhibitors: existing strategies and emerging innovations.

Telomerase, crucial for maintaining telomere length, is an attractive target for cancer therapy due to its role in cellular immortality. Despite three decades of research efforts, no small-molecule telomerase inhibitors have been clinically approved, highlighting the extensive challenges in developing effective telomerase-based therapeutics. This review examines conventional and emerging methods to measure telomerase activity and discusses existing inhibitors, including oligonucleotides and small molecules. Furthermore, this review highlights recent breakthroughs in structural studies of telomerase using cryo-electron microscopy, which can facilitate improved structure-based drug design. Altogether, advancements in structural methodologies and high-throughput screening offer promising prospects for telomerase-based cancer therapeutic development.

Acetylation of PGK1 at lysine 323 promotes glycolysis, cell proliferation, and metastasis in luminal A breast cancer cells

BackgroundIn prior research employing iTRAQ (Isobaric Tags for Relative and Absolute Quantitation) technology, we identified a range of proteins in breast cancer tissues exhibiting high levels of acetylation. Despite this advancement, the specific functions and implications of these acetylated proteins in the context of cancer biology have yet to be elucidated. This study aims to systematically investigate the functional roles of these acetylated proteins with the objective of identifying potential therapeutic targets within breast cancer pathophysiology.MethodsAcetylated targets were identified through bioinformatics, with their expression and acetylation subsequently confirmed. Proteomic analysis and validation studies identified potential acetyltransferases and deacetylases. We evaluated metabolic functions via assays for catalytic activity, glucose consumption, ATP levels, and lactate production. Cell proliferation and metastasis were assessed through viability, cycle analysis, clonogenic assays, PCNA uptake, wound healing, Transwell assays, and MMP/EMT marker detection.ResultsAcetylated proteins in breast cancer were primarily involved in metabolism, significantly impacting glycolysis and the tricarboxylic acid cycle. Notably, PGK1 showed the highest acetylation at lysine 323 and exhibited increased expression and acetylation across breast cancer tissues, particularly in T47D and MCF-7 cells. Notably, 18 varieties acetyltransferases or deacetylases were identified in T47D cells, among which p300 and Sirtuin3 were validated for their interaction with PGK1. Acetylation at 323 K enhanced PGK1's metabolic role by boosting its activity, glucose uptake, ATP production, and lactate output. This modification also promoted cell proliferation, as evidenced by increased viability, S phase ratio, clonality, and PCNA levels. Furthermore, PGK1-323 K acetylation facilitated metastasis, improving wound healing, cell invasion, and upregulating MMP2, MMP9, N-cadherin, and Vimentin while downregulating E-cadherin.ConclusionPGK1-323 K acetylation was significantly elevated in T47D and MCF-7 luminal A breast cancer cells and this acetylation could be regulated by p300 and Sirtuin3. PGK1-323 K acetylation promoted cell glycolysis, proliferation, and metastasis, highlighting novel epigenetic targets for breast cancer therapy.

Antimigratory Effect of Lipophilic Cations Derived from Gallic and Gentisic Acid and Synergistic Effect with 5-Fluorouracil on Metastatic Colorectal Cancer Cells: A New Synthesis Route.

Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world. Standard drugs currently used for the treatment of advanced CRC-such as 5-fluorouracil (5FU)-remain unsatisfactory in their results due to their high toxicity, high resistance, and adverse effects. In recent years, mitochondria have become an attractive target for cancer therapy due to higher transmembrane mitochondrial potential. We synthesized gallic acid derivatives linked to a ten-carbon aliphatic chain associated with triphenylphosphonium (TPP+C10), a lipophilic cationic molecule that induces the uncoupling of the electron transport chain (ETC). Other derivatives, such as gentisic acid (GA-TPP+C10), have the same effects on colorectal cancer cells. Although part of our group had previously reported preparing these structures by a convergent synthesis route, including their application via flow chemistry, there was no precedent for a new methodology for preparing these compounds. In this scenario, this study aims to develop a new linear synthesis strategy involving an essential step of Steglich esterification under mild conditions (open flask) and a high degree of reproducibility. Moreover, the study seeks to associate GA-TPP+C10 with 5FU to evaluate synergistic antineoplastic effects. In addition, we assess the antimigratory effect of GA-TPP+C10 and TPP+C10 using human and mouse metastatic CRC cell lines. The results show a new and efficient synthesis route of these compounds, having synergistic effects in combination with 5FU, increasing apoptosis and enhancing cytotoxic properties. Additionally, the results show a robust antimigratory effect of GATPP+C10 and TPP+C10, reducing the activation pathways linked to tumor progression and reducing the expression of VEGF and MMP-2 and MMP-9, common biomarkers of advanced CRC. Moreover, TPP+C10 and GA-TPP+C10 increase the activity of metabolic signaling pathways through AMPK activation. The data allow us to conclude that these compounds can be used for in vivo evaluations and are a promising alternative associated with conventional therapies for advanced colorectal cancer. Additionally, the reported intermediates of the new synthesis route could give rise to analog compounds with improved therapeutic activity.

Cancer Therapy with Quinoxaline Derivatives: Dual Inhibition of Pi3k and Mtor Signaling Pathways

Quinoxaline is a heterocyclic compound with a benzene ring fused to a pyrazine ring. It learned much about his ability to cure many diseases, including cancer. Phosphoinositide 3kinase (PI3K) and the mTOR (mammalian target of rapamycin) are the 3 essential pathways which regulate the growth, survival, and development of cells. Dysregulation of such pathways is often seen in cancer, making them attractive targets for cancer therapy. In particular, several quinoxaline derivatives show promise as two inhibitors of the mTOR/PI3K signalling pathway, which is often dysregulated in cancer along with many other diseases. One such example is PX866, which has shown activity against several cancers in previous studies. In previous studies, another quinoxaline derivative, PKI587, also showed strong inhibitory activity against mTOR and PI3K. PKI587 was researched in several clinical trials for treating many cancer types, which include non-small cell lung as well as breast cancer. Dual inhibitors of mTOR and PI3K, including quinoxaline derivatives, inhibit cell growth and cancer by blocking the signalling of these two important factors. In recent years, quinoxaline derivatives have emerged as potent dual inhibitors of PI3K and mTOR, and in this review, we explore the latest developments in this area.

The current status and future trends of BET research in oncology

BackgroundBET family proteins are important epigenetic and transcriptional regulators involved in the control of tumorigenesis and development and have become important targets for cancer therapy. However, there is no systematic bibliometric analysis in this field. A visual analysis of the research hotspots and trends of BET is helpful to understand the future development direction. MethodWe used CiteSpace, VOSviewer, and Excel to visualize and analyze the trends regarding authors, journals, countries or regions, highly cited papers, and keywords in the field. ResultThe results included a total of 946 publications. There are many more papers on BET proteins published since 2013. The papers are mainly from 44 countries, led by the U.S. and China. A total of 7381 authors were identified, among which Bradner, J.E. had the greatest number of articles and the greatest influence. Cancer Discovery was the journal with the most citations per article. Our analysis identified the most influential papers in the field, including highly cited papers and citation burst references. The most frequent keywords included ‘expression’, ‘c-Myc’, ‘cancer’, ‘BRD4’, ‘BET inhibition’, ‘resistance’, ‘differentiation’, and ‘JQ1’, which represent the focus of current and developing research fields. ConclusionResearch on BET is thriving. Collaboration and exchanges between countries and institutions must be strengthened in the future, and the mechanisms of BET-related pathways, the relationship between BET and various diseases, and the development of new BET inhibitors have become the major focus of current research and the trend of future research.

Docosahexaenoic acid enhances the treatment efficacy for castration-resistant prostate cancer by inhibiting autophagy through Atg4B inhibition

Autophagy induction in cancer is involved in cancer progression and the acquisition of resistance to anticancer agents. Therefore, autophagy is considered a potential therapeutic target in cancer therapy. In this study, we found that long-chain fatty acids (LCFAs) have inhibitory effects on Atg4B, which is essential for autophagosome formation, through screening based on the pharmacophore of 21f, a recently developed Atg4B inhibitor. Among these fatty acids, docosahexaenoic acid (DHA), a polyunsaturated fatty acid, exhibited the most potent Atg4B inhibitory activity. DHA inhibited autophagy induced by androgen receptor signaling inhibitors (ARSI) in LNCaP and 22Rv1 prostate cancer cells and significantly increased apoptotic cell death. Furthermore, we investigated the effect of DHA on resistance to ARSI by establishing darolutamide-resistant prostate cancer 22Rv1 (22Rv1/Dar) cells, which had developed resistance to darolutamide, a novel ARSI. At baseline, 22Rv1/Dar cells showed a higher autophagy level than parental 22Rv1 cells. DHA significantly suppressed Dar-induced autophagy and sensitized 22Rv1/Dar cells by inducing apoptotic cell death through mitochondrial dysfunction. These results suggest that DHA supplementation may improve prostate cancer therapy with ARSI.

Elucidating the Selective Mechanism of Drugs Targeting Cyclin-Dependent Kinases with Integrated MetaD-US Simulation.

Cyclin-dependent kinases (CDKs), including CDK12 and CDK13, play crucial roles in regulating the cell cycle and RNA polymerase II activity, making them vital targets for cancer therapies. SR4835 is a selective inhibitor of CDK12/13, showing significant potential for treating triple-negative breast cancer. To elucidate the selective mechanism of SR4835 among three CDKs (CDK13/12/9), we developed an innovative enhanced sampling method, integrated well-tempered metadynamics-umbrella sampling (IMUS). IMUS synergistically combines the comprehensive pathway exploration capability of well-tempered metadynamics (WT-MetaD) with the precise free energy calculation capability of umbrella sampling, enabling the efficient and accurate characterization of drug-target interactions. The accurate calculation of binding free energy and the detailed analysis of the kinetic mechanism of the drug-target interaction using IMUS successfully elucidate the drug selectivity mechanism targeting the three CDKs, showing that the selectivity is primarily arising from differences in the stability of H-bonds within the Hinge region of the kinases and the interaction patterns during the protein-ligand recognition process. These findings also underscore the utility of IMUS in efficiently and accurately capturing drug-target interaction processes with clear mechanisms.

Multiscale Computational Analysis of the Effect of Taxol on Microtubule Mechanics.

Microtubules (MTs) are widely recognized as targets for cancer therapies. They are directly related to unique mechanical properties, closely dependent on MT architecture and tubulin molecular features. Taxol is known to affect tubulin interactions resulting in the stabilization of the MT lattice, and thus the hierarchical organization stability, mechanics, and function. A deeper understanding of the molecular mechanisms through which taxol modulates intertubulin interactions in the MT lattice, and consequently, its stability and mechanical response is crucial to characterize how MT properties are regulated by environmental factors, such as interacting ligands. In this study, a computational analysis of the effect of taxol on the MT was performed at different scales, combining molecular dynamics simulation, dynamical network analysis, and elastic network modeling. The results show that the taxol-induced conformational differences at the M-loop region increase the stability of the lateral interactions and the amount of surface in contact between laterally coupled tubulins. Moreover, the conformational rearrangements in the taxane binding site result in a different structural communication pattern. Finally, the different conformation of the tubulin heterodimers and the stabilized lateral interactions resulted in a tendency toward higher deformation of the vibrating MT in the presence of taxol. Overall, this work provides additional insights into taxol-induced stabilization and relates the conformational changes at the tubulin level to the MT mechanics. Besides providing useful insights into taxol effect on MT mechanics, a methodological framework that could be used to characterize the effects of other MT stabilizing agents is presented.

Walrycin B, as a novel separase inhibitor, exerts potent anticancer efficacy in a mouse xenograft model

Proper chromosome segregation during cell division relies on the timely dissolution of chromosome cohesion. Separase (EC3.4.22.49), a cysteine protease, plays a critical role in mitosis by cleaving the kleisin subunit of cohesin, thereby presenting a promising target for cancer therapy. However, challenges in isolating active human separase suitable for high-throughput screening have limited the identification of effective inhibitors. Here, we conducted a high-throughput screening of small-molecule inhibitors using the protease domain of Chaetomium thermophilum separase (ctSPD), which not only shares significant sequence similarity with human separase but is also readily available. After conducting a primary screening of a library containing 9,172 compounds and subsequent validation using human separase, we identified walrycin B and its analogs, toxoflavin, 3-methyltoxoflavin, and 3-phenyltoxoflavin, as potent inhibitors of human separase. Subsequent microscale thermophoresis assays and molecular dynamics simulations revealed that walrycin B binds to the active site of separase and competes with substrates for binding. Additionally, cell-based studies showed that walrycin B and its analogs effectively induce cell cycle arrest at the M phase, activate apoptosis, and ultimately lead to cell death in mitosis. Finally, in a mouse xenograft model, walrycin B exhibited significant antitumor efficacy with minimal side effects. Together, these findings highlight the therapeutic potential of walrycin B for cancer treatment and its utility as a chemical tool in future studies involving separase.

The feedback loop between MTA1 and MTA3/TRIM21 modulates stemness of breast cancer in response to estrogen

The metastasis-associated protein (MTA) family plays a crucial role in the development of breast cancer, a common malignancy with a high incidence rate among women. However, the mechanism by which each member of the MTA family contributes to breast cancer progression is poorly understood. In this study, we aimed to investigate the roles of MTA1, MTA3, and tripartite motif-containing 21 (TRIM21) in the proliferation, invasion, epithelial-mesenchymal transition (EMT), and stem cell-like properties of breast cancer cells in vivo and in vitro. The molecular mechanisms of the feedback loop between MTA1 and MTA3/TRIM21 regulated by estrogen were explored using Chromatin immunoprecipitation (ChIP), luciferase reporter, immunoprecipitation (IP), and ubiquitination assays. These findings demonstrated that MTA1 acts as a driver to promote the progression of breast cancer by repressing the transcription of tumor suppressor genes, including TRIM21 and MTA3. Conversely, MTA3 inhibited MTA1 transcription and TRIM21 regulated MTA1 protein stability in breast cancer. Estrogen disrupted the balance between MTA1 and MTA3, as well as between MTA1 and TRIM21, thereby affecting stemness and the EMT processes in breast cancer. These findings suggest that MTA1 plays a vital role in stem cell fate and the hierarchical regulatory network of EMT through negative feedback loops with MTA3 or TRIM21 in response to estrogen, supporting MTA1, MTA3, and TRIM21 as potential prognostic biomarkers and MTA1 as a treatment target for future breast cancer therapies.

The upregulation of protein disulfide isomerase (PDI) and its potential usage in drug-targeted therapy for breast cancer

Breast cancer is the leading cause of cancer death among women worldwide. As of the end of 2020, there were 2.3 million women diagnosed with breast cancer and 685 000 deaths globally. Chemotherapy is a common treatment for breast cancer although it was known to be associated with many side effects. It is believed that such treatment can be improved by drug targeted therapy. Recently we have carried out a preliminary study on proteomics analysis of 25 pair of surgically removed breast cancerous tissues and normal tissues from patients. Differentially proteins expression between the types of tissues was done by 2D-gel electrophoresis separation followed by protein profiles mapping. The identity of the targeted protein spots was analysed by LC/MS/MS and protein database search. The data was then confirmed by Western blots. Subsequently, immunocytostaining experiments were carried out to determine the cellular location of the targeted proteins. A few proteins were found significantly (p <0.05) upregulated > 2 folds in breast cancerous tissues compared to breast normal tissues. Two of the up-regulated proteins, namely HSP60 and PDI were upregulated in stage 2, stage 3, T2, T3, N2, and N3 breast cancers. The immunocytostaining revealed the extracellular location of these proteins, while the strong immunoreactivity of PDI with its anti-PDI antibody marked it as a usefulness target for breast cancer therapy.

A New Renieramycin T Right-Half Analog as a Small Molecule Degrader of STAT3.

Constitutive activation of STAT3 contributes to tumor development and metastasis, making it a promising target for cancer therapy. (1R,4R,5S)-10-hydroxy-9-methoxy-8,11-dimethyl-3-(naphthalen-2-ylmethyl)-1,2,3,4,5,6-hexahydro-1,5-epiminobenzo[d]azocine-4-carbonitrile, DH_31, a new derivative of the marine natural product Renieramycin T, showed potent activity against H292 and H460 cells, with IC50 values of 5.54 ± 1.04 µM and 2.9 ± 0.58 µM, respectively. Structure-activity relationship (SAR) analysis suggests that adding a naphthalene ring with methyl linkers to ring C and a hydroxyl group to ring E enhances the cytotoxic effect of DH_31. At 1-2.5 µM, DH_31 significantly inhibited EMT phenotypes such as migration, and sensitized cells to anoikis. Consistent with the upregulation of ZO1 and the downregulation of Snail, Slug, N-cadherin, and Vimentin at both mRNA and protein levels, in silico prediction identified STAT3 as a target, validated by protein analysis showing that DH_31 significantly decreases STAT3 levels through ubiquitin-proteasomal degradation. Immunofluorescence and Western blot analysis confirmed that DH_31 significantly decreased STAT3 and EMT markers. Additionally, molecular docking suggests a covalent interaction between the cyano group of DH_31 and Cys-468 in the DNA-binding domain of STAT3 (binding affinity = -7.630 kcal/mol), leading to destabilization thereafter. In conclusion, DH_31, a novel RT derivative, demonstrates potential as a STAT3-targeting drug that significantly contribute to understanding of the development of new targeted therapy.

Ribosome Biogenesis and Cancer: Insights into NOB1 and PNO1 Mechanisms.

Post-transcriptional modifications (PTMs) are pivotal in the regulation of gene expression, and pseudouridylation is emerging as a critical player. This modification, facilitated by enzymes such as NOB1 (PNO1), is integral to ribosome biogenesis. PNO1, in collaboration with the NIN1/RPN12 binding protein 1 homolog (NOB1), is vital for the maturation of ribosomes, transitioning 20S pre-rRNA into functional 18S rRNA. Recent studies have highlighted PNO1's potential involvement in cancer progression; however, its underlying mechanisms remain unclear. Relentless growth characterizing cancer underscores the burgeoning significance of epitranscriptomic modifications, including pseudouridylation, in oncogenesis. Given PNO1's emerging role, it is imperative to delineate its contribution to cancer development to identify novel therapeutic interventions. This review summarizes the current literature regarding the role of PNO1 in cancer progression and its molecular underpinnings in oncogenesis. Overexpression of PNO1 was associated with unfavorable prognosis and increased tumor malignancy. At the molecular level, PNO1 facilitates cancer progression by modulating mRNA stability, alternative splicing, and translation efficiency. Its role in pseudouridylation of oncogenic and tumor-suppressor transcripts further underscores its significance in cancer biology. Although disruption of ribosome biogenesis is known to precipitate oncogenesis, the precise mechanisms by which these alterations contribute to cancer remain unclear. This review elucidates the intricate process of ribosomal small subunit maturation, highlighting the roles of crucial ribosomal proteins (RPs) and RNA-binding proteins (RBPs) as well as the positioning and function of NOB1 and PNO1 within the 40S subunit. The involvement of these components in the maturation of the small subunit (SSU) and their significance in the context of cancer therapeutics has been thoroughly explored. PNO1's burgeoning significance in oncology makes it a potential target for cancer therapies. Strategies aimed at modulating PNO1-mediated pseudouridylation may provide new avenues for cancer treatment. However, further research is essential to unravel the complete spectrum of PNO1 mechanisms in cancer and harness this knowledge for the development of targeted and more efficacious anticancer therapies.

Synthetic lethality between ATR and POLA1 reveals a potential new target for individualized cancer therapy

The ATR-CHK1 pathway plays a fundamental role in the DNA damage response and is therefore an attractive target in cancer therapy. The antitumorous effect of ATR inhibitors is at least partly caused by synthetic lethality between ATR and various DNA repair genes. In previous studies, we have identified members of the B-family DNA polymerases as potential lethal partner for ATR, i.e. POLD1 and PRIM1. In this study, we validated and characterized the synthetic lethality between ATR and POLA1.First, we applied a model of ATR-deficient DLD-1 human colorectal cancer cells to confirm synthetic lethality by using chemical POLA1 inhibition. Analyzing cell cycle and apoptotic markers via FACS and Western blotting, we were able to show that apoptosis and S phase arrest contributed to the increased sensitivity of ATR-deficient cancer cells towards POLA1 inhibitors. Importantly, siRNA-mediated POLA1 depletion in ATR-deficient cells caused similar effects in regard to impaired cell viability and cumulation of apoptotic markers, thus excluding toxic effects of chemical POLA1 inhibition. Conversely, we demonstrated that siRNA-mediated POLA1 depletion sensitized several cancer cell lines towards chemical inhibition of ATR and its main effector kinase CHK1.In conclusion, the synthetic lethality between ATR/CHK1 and POLA1 might represent a novel and promising approach for individualized cancer therapy: First, alterations of POLA1 could serve as a screening parameter for increased sensitivity towards ATR and CHK1 inhibitors. Second, alterations in the ATR-CHK1 pathway might predict in increased sensitivity towards POLA1 inhibitors.

A Two-Pronged Nanostrategy of Iron Metabolism Disruption to Synergize Tumor Therapy by Triggering the Paraptosis-Apoptosis Hybrid Pathway.

Iron metabolism has emerged as a promising target for cancer therapy; however, the innate metabolic compensatory capacity of cancer cells significantly limits the effectiveness of iron metabolism therapy. Herein, bioactive gallium sulfide nanodots (GaSx), with dual functions of "reprogramming" and "interfering" iron metabolic pathways, were successfully developed for tumor iron metabolism therapy. The constructed GaSx nanodots ingeniously harness hydrogen sulfide (H2S) gas, which is released in response to the tumor microenvironment, to reprogram the inherent transferrin receptor 1 (TfR1)-ferroportin 1 (FPN1) iron metabolism axis in cancer cells. Concurrently, the gallium ions (Ga3+) derived from GaSx act as a biochemical "Trojan horse", mimicking the role of iron and displacing it from essential biomolecular binding sites, thereby influencing the fate of cancer cells. By leveraging the dual mechanisms of Ga3+-mediated iron disruption and H2S-facilitated reprogramming of iron metabolic pathways, GaSx prompted the initiation of a paraptosis-apoptosis hybrid pathway in cancer cells, leading to marked suppression of tumor proliferation. Importantly, the dysregulation of iron metabolism induced by GaSx notably increased tumor cell susceptibility to both chemotherapy and immune checkpoint blockade (ICB) therapy. This study underscores the therapeutic promise of gas-based interventions and metal ion interference strategies for the tumor metabolism treatment.