Current Cancer Drug Targets - Volume 23, Issue 3, 2023

Phosphoserine aminotransferase 1 (PSAT1) catalyzes 3-phosphohydroxylpyruvate and glutamate into 3-phosphoserine and α-ketoglutamate. It integrates metabolic pathways critical for cell proliferation, survival, migration and epigenetics, such as glycolysis, de novo serine synthesis, citric acid cycle and one-carbon metabolism. The level of this enzyme has been disclosed to be closely related to the occurrence, progression and prognosis of cancers like non-small cell lung cancer, colorectal cancer, esophageal squamous cell carcinoma, breast cancer, etc. via metabolic catalyzation, PSAT1 offers anabolic and energic supports for these tumor cells, affecting their proliferation, survival, autophagy, migration and invasion. Such functions also influence the epigenetics of other noncancerous cells and drive them to serve tumor cells. Moreover, PSAT1 exerts a non-enzymatic regulation of the IGF1 pathway and nuclear PKM2 to promote EMT and cancer metastasis. Genetically manipulating PSAT1 alters tumor progression in vitro and in vivo. This paper reviews the role and action mechanism of PSAT1 in tumor biology and chemotherapy as well as the regulation of PSAT1 expression, exhibiting the perspective for PSAT1 as a new molecular marker and target for cancer diagnosis and treatment.

Tumor cells develop a high demand for inorganic phosphate (Pi) due to their high growth rates and energy requirements. Serum Pi concentrations in cancer patients have been found to be two to four times higher than baseline levels in healthy individuals. Twofold Pi accumulation was observed in breast cancer cells in the mouse tumor microenvironment. In the breast tumoral microenvironment, ectonucleotidases and ectophosphatases—presenting catalytic sites facing the extracellular environment—could be involved in the extracellular release of Pi to be internalized by Pi transporters to fuel the high energy requirement typical of cancer cells. Two Pi transporters were characterized in breast cancer cells (Na+-dependent and H+-dependent) with strong associations with tumor processes such as proliferation, migration, adhesion, and epithelium-mesenchymal transition (EMT). Moreover, a high extracellular Pi concentration stimulates ROS production in triple-negative breast cancer cells by Pi transport stimulation. Several compounds show a potent ability to inhibit ectonucleotidases, ectophosphatases, Pi transporters, and Pi-modulated signal pathways in breast cancer cells and regulate proliferation, migration, adhesion, and EMT. This review article aimed to gather the relevant experimental records regarding Pi's effects on the breast cancer microenvironment and points to possible inhibitors for ectonucleotidases, ectophosphatases, Pi transporters, and Pi-modulated signal pathways as potential chemotherapeutic agents or Pi acting as a potent enhancer of classical chemical-induced cytotoxicity in triple-negative breast cancer cells.

Chimeric antigen receptor (CAR T) cell treatment for solid tumours faces significant challenges. CAR T cells are unable to pass the vascular barrier in tumours due to a lack of endothelial leukocyte adhesion molecules. The invasion, activity, and durability of CAR T cells may be hampered by additional immunosuppressive mechanisms present in the solid tumour environment. The use of CAR T cells to attack cancer vascular endothelial metabolic targets from within the blood may simplify the fight against cancer. These are the principles that govern our examination of CAR T cell treatment for tumor cells, with a specific eye toward tumour venous delivery. CAR T cells may also be designed such that they can be readily, safely, and successfully transferred.

Background: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths globally. This study aimed to provide a comprehensive investigation to screen and identify biomarkers for predicting HCC. Methods: Firstly, the bioinformatics technique was applied to screen potential HCC-related genes, and the relationships between BZW2, CDT1, IVD expression and survival rate and clinicopathological factors were assessed. Afterward, qRT-PCR, western blot and immunohistochemistry were employed to validate the expression of BZW2, CDT1, and IVD in clinical resected cancer specimens. Furthermore, in vitro assays, cell cycle, apoptosis, colony formation and scratch experiments were performed to detect the effects of si-BZW2, si-CDT1 and oe-IVD in HCC cells. In vivo experiments, tumor volume and weight were measured to assess the anti-tumor effect of si-BZW2, si-CDT1 and oe-IVD in HCCtumor- bearing mice. Results: Bioinformatics analysis indicated that HCC patients with high expression of BZW2, CDT1 and low expression of IVD have a poor prognosis and unfavorable clinicopathological factors. Similarly, clinical sample analysis revealed that BZW2 and CDT1 expression were increased while IVD expression was decreased in HCC tissues. Meanwhile, in vitro experiments found that si-BZW2, si- CDT1 and oe-IVD promoted apoptosis and inhibited the colony formation and migration of HCC cells. As expected, in vivo experiments demonstrated that si-BZW2, si-CDT1 and oe-IVD could inhibit tumor growth. Conclusion: Increased BZW2, CDT1 levels, and decreased IVD levels could act as biomarkers for predicting HCC. Furthermore, targeting BZW2, CDT1, and IVD may offer a new approach to treat HCC.

Objective: Human breast cancer is among one major health concerns with high prevalence and mortality among women worldwide. Various cellular signaling pathways are implicated in carcinogenesis. One of the major pathways that affect the downstream cellular growth cascades is Mevalonate pathway (MVA). The inhibition of MVA is therapeutically beneficial for various cancers. Pamidronate (PAM) (MVA inhibitor), a nitrogen-containing bisphosphosphonate, is an antiresorptive FDAapproved drug. The objective of our study was to explore adjuvant therapy using a combination of PAM and an alkylating agent, Temozolomide (TMZ) against breast cancer. Methods: We have examined the differential gene and protein expression in response to the combination treatment strategy. For gene expression analysis RT-qPCR and for proteomic study, twodimensional gel electrophoresis and mass spectrometry techniques were utilized. Results: Combination treatment (PAM+TMZ) showed more pronounced cytotoxic effect as compared to single agent treatment. Our results indicate that MVA pathway regulatory genes (FDFT1, FDPS, KRAS) are significantly (p<0.05) downregulated in combination-treated breast cancer cells. The differential proteomic analysis showed lower expression of GFAP, PPA1 and TRIM68 proteins after synergistic treatment whereas, these proteins are found to be up-regulated in multiple cancers. Conclusion: The present study reveals that a combination of PAM and TMZ produces an effective anti-cancerous effect on breast cancer cells. Therefore, this novel therapeutic regimen is likely to provide a better treatment strategy for breast cancer.

Aims: Generation of the human anti-MUC1 peptide through neural network training and monomeric design method. Analyzing 9-mer peptide potential computationally for treatment of HER2-positive breast cancer. Background: With the advancements of cancer genome atlas project (TCGA), cancer dependancy project (DepMap) and human protein atlas (HPA), large-scale datasets are generated for oncology studies. However, after development of redefined breast cancer drug targets, there are key issues in successful breast cancer treatments that needed to be pursued which paved the pathway for new approaches or strategies. In that respect, our research data aimed to represent a new aspect of breast cancer drug development studies. Objective: Extract human MUC1 sequences from various databases. Perform neural networking method for novel peptides sequences. Analyze the potentiality of generated heteroclitic peptide sequences for suitable vaccine candidate for breast cancer treatment. Methods: Input scaffolds of protein database (PDB) files for human MUC1 were retrieved and loaded into Evo design server with monomeric based design option. Further, neural network training approaches were followed and other computational tools were used for alignment-independent prediction of protective antigens and subunit vaccines potency of designed heteroclitic peptides. Results: Study findings revealed two human anti-MUC1 heteroclitic peptides of 9mers (WAVWTYVSV, FMSFYIMNL), which showed the lowest energy cluster and sequence identity, normalized relative error rate of secondary structure, solvent accessibility, backbone torsion angles for neural networking and RMSD values in evolutionary profiling, and online MHCPred IC50 interaction values. VaxiGen v2.0 server revealed subunit vaccine potency values of in-silico designed two heteroclitic peptides were 0.1551 (WAVWTYVSV) and 0.3508 (FMSFYIMNL) with a threshold value of 0.5 followed by AllerTOP v2.0 for their allergenicity nature in immunogenic reactions. Conclusion: Computationally designed heteroclitic peptide WAVWTYVSV indicated promising values which can be utilised as drug delivery or tumour marker candidate in the treatment of human breast cancer by eliciting lyse of tumor cells.

Background: Autophagy disorders are linked to human cancer, and the details of their mechanisms remain unclear. Objective: To investigate the regulatory role of PRMT5 in the autophagy of breast cancer cells. Methods: Human breast adenocarcinoma cell lines (MDA-MB-231, MCF7) were cultured. Plasmids of overexpression and down-regulation of PRMT5 were transfected into MDA-MB-231 and MCF7 cells. The MTT assay was used to determine the proliferation of MDA-MB-231 and MCF7 cells. A western blotting assay was used to verify the expression of autophagy-associated molecules. Immunofluorescence was applied to observe the expression of GFP-LC3. Results: The expression of PRMT5 decreased the sensitivity to rapamycin and nutrient deprivation. PRMT5 acts as an oncogene to promote cell proliferation and influences migration and stamness. PRMT5 expression elevated the autophagic activity initiated by EBSS and Rapamycin. PRMT5 was necessary and sufficient to enhance stress-induced autophagy. PRMT5 could improve several autophagy- related gene expressions. Atg5 expression could be regulated by activating the PRMT5 and PDCD4 molecules. The PRMT5 molecule could mediate the regulation of ULK1 expression. Conclusion: PRMT5 influenced multiple stages of autophagy in controlling autophagy and tumorigenesis. Autophagy-related PRMT5 might be a respected target for therapeutic interventions in cancers. This study would provide new ideas for treating and selecting breast cancer targets.