bims-polyam 2024-12-08 papers

Issue of 2024–12–08
six papers selected by
Sebastian J. Hofer, University of Graz

Cancer Innov. 2025 Feb;4(1): e138

Subtype-specific transcription factors affect polyamine metabolism and the tumor microenvironment in breast cancer.

Background: Polyamines play important roles in cell growth and proliferation. Polyamine metabolism genes are dysregulated in various tumors. Some polyamine metabolism genes are regulated by transcription factors. However, the transcription factors that regulate polyamine metabolism genes have not been completely identified. Additionally, whether any of the transcriptional regulations depend on tumor heterogeneity and the tumor microenvironment has not been investigated.
Methods: We used bulk RNA-seq data to identify dysregulated polyamine metabolism genes and their transcription factors across breast cancer subtypes. Genes highly correlated with polyamine changes were obtained, and their subtype-specific expressions were checked in tumor microenvironment cells using single-cell RNA (scRNA)-seq data. Gene Ontology enrichment analysis was used to explore their molecular functions and biological processes, and survival analysis was used to examine the impact of these genes on therapeutic outcome.
Results: We first analyzed the dysregulation of polyamine synthesis, catabolism, and transport in four breast cancer subtypes. Genes such as AGMAT and CAV1 were dysregulated across all subtypes, while APRT, SAT1, and other genes were dysregulated in the more lethal subtypes. Among the dysregulated genes of polyamine metabolism, we focused on three genes (SRM, APRT, and SAT1) and identified their transcription factors (SPI1 and IRF1 correspond to SAT1, and IRF3 corresponds to SRM and APRT). With scRNA-seq data, we verified that these three transcription factors also regulated these three polyamine metabolism genes in the tumor microenvironment. Both bulk RNA-seq and scRNA-seq data indicated that these genes were specifically upregulated in high-risk breast cancer subtypes, such as the basal-like type. High expression of these genes corresponded to worse outcomes in the basal-like subtype under chemotherapy and radiation treatment.
Conclusion: Our work identified three subtype-specific transcription factors that regulate three polyamine metabolism genes in high-risk breast cancer subtypes and the tumor microenvironment. Our results deepen the understanding of the role of polyamine metabolism in breast cancer and may help the clinical therapy of advanced breast cancer subtypes.

Keywords: breast cancer; immune cells; polyamine metabolism; transcription factor; tumor microenvironment

DOI: https://doi.org/10.1002/cai2.138

Electrophoresis. 2024 Dec 06.

Quantitative Endogenous Polyamine Analysis via Capillary Electrophoresis/Mass Spectrometry: Characterization and Practical Considerations.

Cameron J Kaminsky, Jericha Mill, Thomas Raife, Lingjun Li.

Commonly used analytical techniques for polyamine analysis, including derivatization and mixed-mode liquid chromatography (LC), have inherent disadvantages. Capillary electrophoresis (CE) is uniquely suited to analyze small, highly charged molecules because analytes are separated on the basis of their electrophoretic mobility, not polarity or association with a stationary phase. Microfluidic CE-mass spectrometry (mCE-MS) is a relatively recent addition to commercially available CE offerings that streamlines traditional CE-MS interfacing and has the potential to improve upon classic CE challenges to robustness and reproducibility. MS instrument choice and scanning parameters are strongly influenced by a need for high acquisition rate to adequately sample CE peaks. Alternatively, isotachophoresis on loading can be intentionally avoided to produce sufficiently wide peaks. The mCE platform utilized here performed very well in many metrics; a limit of detection (LOD) as low as 0.25 ng/mL was achieved for spermidine, and endogenous spermidine was easily detected in blood with this method. Both of these are challenging tasks for any separation technique and demonstrate a strong use case for the platform. During experimentation, various idiosyncrasies in the commercial CE-MS interface resulted in extensive chip-to-chip variability in both peak shape and LOD, complicating the application to robust absolute quantitation. Practical guidance for similar analyses is provided.

Keywords: microfluidic; polyamine; quantitation; spermidine

DOI: https://doi.org/10.1002/elps.202400165

Comput Methods Biomech Biomed Engin. 2024 Dec 02. 1-14

Identification of polyamine metabolism-related prognostic biomarkers for predicting breast cancer prognosis, immune microenvironment, and candidate drugs.

Dejie Zhang, Pengfei Li, Xinjie Du, Ming Zhang, Qi Li, Qicai Wang, Xingfeng Tu, Guoliang Lin.

In this study, polyamine metabolism related genes (PMRGs) were used to establish a breast cancer (BC) prognostic model. Using PMRGs, TCGA BC samples were divided into cluster1 and cluster2. A 13-gene BC prognostic model was constructed by screening differential genes. High-risk BC patients exhibited heightened immunoinfiltration levels, potentially impeding immunotherapy responses. Drug response predicted that BC patients in the low-risk group might benefit more from chemotherapy and targeted therapy. In conclusion, a novel 13-gene BC prognostic risk model based on PMRGs was established to effectively predict prognosis, immune microenvironment, and drug therapy response in patients with BC.

Keywords: Breast cancer; drug response prediction; immune microenvironment; polyamine metabolism; prognostic model

DOI: https://doi.org/10.1080/10255842.2024.2433112

PLoS Negl Trop Dis. 2024 Dec 02. 18(12): e0012690

An experimental target-based platform in yeast for screening Plasmodium vivax deoxyhypusine synthase inhibitors.

Suélen Fernandes Silva, Angélica Hollunder Klippel, Sunniva Sigurdardóttir, Sayyed Jalil Mahdizadeh, Ievgeniia Tiukova, Catarina Bourgard, Luis Carlos Salazar-Alvarez, Heloísa Monteiro do Amaral Prado, Renan Vinicius de Araujo, Fabio Trindade Maranhão Costa, Elizabeth Bilsland, Ross D King, Katlin Brauer Massirer, Leif A Eriksson, Mário Henrique Bengtson, Cleslei Fernando Zanelli, Per Sunnerhagen.

The enzyme deoxyhypusine synthase (DHS) catalyzes the first step in the post-translational modification of the eukaryotic translation factor 5A (eIF5A). This is the only protein known to contain the amino acid hypusine, which results from this modification. Both eIF5A and DHS are essential for cell viability in eukaryotes, and inhibiting DHS is a promising strategy to develop new therapeutic alternatives. DHS proteins from many are sufficiently different from their human orthologs for selective targeting against infectious diseases; however, no DHS inhibitor selective for parasite orthologs has previously been reported. Here, we established a yeast surrogate genetics platform to identify inhibitors of DHS from Plasmodium vivax, one of the major causative agents of malaria. We constructed genetically modified Saccharomyces cerevisiae strains expressing DHS genes from Homo sapiens (HsDHS) or P. vivax (PvDHS) in place of the endogenous DHS gene from S. cerevisiae. Compared with a HsDHS complemented strain with a different genetic background that we previously generated, this new strain background was ~60-fold more sensitive to an inhibitor of human DHS. Initially, a virtual screen using the ChEMBL-NTD database was performed. Candidate ligands were tested in growth assays using the newly generated yeast strains expressing heterologous DHS genes. Among these, two showed promise by preferentially reducing the growth of the PvDHS-expressing strain. Further, in a robotized assay, we screened 400 compounds from the Pathogen Box library using the same S. cerevisiae strains, and one compound preferentially reduced the growth of the PvDHS-expressing yeast strain. Western blot revealed that these compounds significantly reduced eIF5A hypusination in yeast. The compounds showed antiplasmodial activity in the asexual erythrocyte stage; EC50 in high nM to low μM range, and low cytotoxicity. Our study demonstrates that this yeast-based platform is suitable for identifying and verifying candidate small molecule DHS inhibitors, selective for the parasite over the human ortholog.

DOI: https://doi.org/10.1371/journal.pntd.0012690

Diabetes. 2024 Dec 02. pii: db240501. [Epub ahead of print]

Blocking adipocyte YY1 decouples thermogenesis from beneficial metabolism by promoting spermidine production.

Chen Qiu, Yu Lu, Suyang Wu, Wenli Guo, Jiahao Ni, Jiyuan Song, Zichao Liu, Xiaoai Chang, Kai Wang, Peng Sun, Qian Zhang, Shufang Yang, Kai Li.

The accumulation of mitochondria in thermogenic adipose tissue (i.e., brown and beige fat) increases energy expenditure, which can aid in alleviating obesity and metabolic disorders. However, recent studies have shown that knocking out key proteins required to maintain mitochondrial function inhibits the energy expenditure in thermogenic fat, and yet the knockout mice are unexpectedly protected from developing obesity or metabolic disorders when fed a high-fat diet (HFD). In the present study, non-biased sequencing-based screening revealed the importance of YY1 in the transcription of electron transport chain genes and the enhancement of mitochondrial function in thermogenic adipose tissue. Specifically, adipocyte YY1 null (YAKO) mice showed lower energy expenditure and were intolerant to cold stress. Interestingly, YAKO mice showed alleviation of HFD-induced metabolic disorders, which can be attributed to a suppression of adipose tissue inflammation. Metabolomic analysis revealed that blocking YY1 directed glucose metabolism toward lactate, enhanced the uptake of glutamine, and promoted the production of anti-inflammatory spermidine. Conversely, blocking spermidine production in YAKO mice reversed their resistance to HFD-induced disorders. Thus, although blocking adipocyte YY1 impairs the thermogenesis, it promotes spermidine production and alleviates adipose tissue inflammation, therefore leads to an uncoupling of adipose tissue energy expenditure from HFD-induced metabolic disorders.

DOI: https://doi.org/10.2337/db24-0501

Chem Biodivers. 2024 Dec 04. e202401873

Design, Synthesis and Biological Evaluation of Naphthalimide-Polyamine Conjugate as a Potential Anti-Colorectal Cancer Agent.

Fujun Dai, Yue Cao, Chenguang Zhu, Yibing Li, Xiaoxuan Ma, Senzhen Wang, Haizhen Liu, Xiaoya Xie, Lei Gao, Yanming Wang, Chaojie Wang.

Colorectal cancer is the second most common cause of cancer-related death worldwide with a rising incidence, highlighting an urgent need for novel therapeutics. In this study, we developed several polyamine conjugates. Compound 6 (C6) was selected as the lead compound and was evaluated for anticancer activity in vitro and in vivo. In vitro experiments showed that C6 inhibited cell proliferation, colony formation, migration, and invasion of colorectal cancer cells while inducing apoptosis, pyroptosis, and autophagosomes formation. Genetic or pharmacological inhibition of autophagy weakened C6-induced apoptosis and gasdermin E (GSDME)-dependent pyroptosis. Inactivation of caspase 3 activity by AC-DEVD-CHO decreased the levels of N-terminal GSDME induced by C6. Furthermore, animal models exhibited suppressed tumor growth and dissemination after treatment with C6. Taken together, our findings highlight C6 as a potential drug against colorectal cancer.

Keywords: Apoptosis; Colorectal cancer; Pyroptosis; autophagy; lysosomes

DOI: https://doi.org/10.1002/cbdv.202401873