Enhancing the anticancer effect of androgen deprivation therapy by monocarboxylate transporter 1 inhibitor in prostate cancer cells.

BACKGROUND: Tumor initiation and progression necessitate a metabolic shift in cancer cells. Consequently, the progression of prostate cancer (PCa), a leading cause of cancer-related deaths in males globally, involves a shift from lipogenic to glycolytic metabolism. Androgen deprivation therapy (ADT) serves as the standard treatment for advanced-stage PCa. However, despite initial patient responses, castrate resistance emerges ultimately, necessitating novel therapeutic approaches. Therefore, in this study, we aimed to investigate the role of monocarboxylate transporters (MCTs) in PCa post-ADT and evaluate their potential as therapeutic targets. METHODS: PCa cells (LNCaP and C4-2 cell line), which has high prostate-specific membrane antigen (PSMA) and androgen receptor (AR) expression among PCa cell lines, was used in this study. We assessed the expression of MCT1 in PCa cells subjected to ADT using charcoal-stripped bovine serum (CSS)-containing medium or enzalutamide (ENZ). Furthermore, we evaluated the synergistic anticancer effects of combined treatment with ENZ and SR13800, an MCT1 inhibitor. RESULTS: Short-term ADT led to a significant upregulation in folate hydrolase 1 (FOLH1) and solute carrier family 16 member 1 (SLC16A1) gene levels, with elevated PSMA and MCT1 protein levels. Long-term ADT induced notable changes in cell morphology with further upregulation of FOLH1/PSMA and SLC16A1/MCT1 levels. Treatment with ENZ, a nonsteroidal anti-androgen, also increased PSMA and MCT1 expression. However, combined therapy with ENZ and SR13800 led to reduced PSMA level, decreased cell viability, and suppressed expression of cancer stem cell markers and migration indicators. Additionally, analysis of human PCa tissues revealed a positive correlation between PSMA and MCT1 expression in tumor regions. CONCLUSIONS: Our results demonstrate that ADT led to a significant upregulation in MCT1 levels. However, the combination of ENZ and SR13800 demonstrated a promising synergistic anticancer effect, highlighting a potential therapeutic significance for patients with PCa undergoing ADT.

Covalent coupling of functionalized outer membrane vesicles (OMVs) to gold nanoparticles.

Outer membrane vesicle-functionalized nanoparticles (OMV-NPs) have attracted significant interest, especially regarding drug delivery applications and vaccines. Here, we report on novel OMV-NPs by applying bioorthogonal click reaction for encapsulating gold nanoparticles (NPs) within outer membrane vesicles (OMVs) by covalent coupling. For this purpose, outer membrane protein A (OmpA), abundant in large numbers (due to 100,000 copies/cell [1]) in OMVs, was modified via the incorporation of the unnatural amino acid p-azidophenylalanine. The azide group was covalently coupled to alkyne-functionalized NPs after incorporation into OmpA. A simplified procedure using low-speed centrifugation (1,000 x g) was developed for preparing OMV-NPs. The OMV-NPs were characterized by zeta potential, Laurdan-based lipid membrane dynamics studies, and the enzymatic activity of functionalized OMVs with surface-displayed nicotinamide adenine dinucleotide oxidase (Nox). In addition, OMVs from attenuated bacteria (ClearColiTM BL21(DE3), E. coli F470) with surface-displayed Nox or antibody fragments were prepared and successfully coupled to AuNPs. Finally, OMV-NPs displaying single-chain variable fragments from a monoclonal antibody directed against epidermal growth factor receptor were applied to demonstrate the feasibility of OMV-NPs for tumor cell targeting.

Impact of glucose metabolism on PD-L1 expression in sorafenib-resistant hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality worldwide. Programmed cell death ligand-1 (PD-L1) is an immune checkpoint protein that binds to programmed cell death-1 (PD-1), which is expressed in activated T cells and other immune cells and has been employed in cancer therapy, including HCC. Recently, PD-L1 overexpression has been documented in treatment-resistant cancer cells. Sorafenib is a multikinase inhibitor and the only FDA-approved treatment for advanced HCC. However, several patients exhibit resistance to sorafenib during treatment. This study aimed to assess the effect of glucose deprivation on PD-L1 expression in HCC cells. We used PD-L1-overexpressing HepG2 cells and IFN-γ-treated SK-Hep1 cells to explore the impact of glycolysis on PD-L1 expression. To validate the correlation between PD-L1 expression and glycolysis, we analyzed data from The Cancer Genome Atlas (TCGA) and used immunostaining for HCC tissue analysis. Furthermore, to modulate PD-L1 expression, we treated HepG2, SK-Hep1, and sorafenib-resistant SK-Hep1R cells with rapamycin. Here, we found that glucose deprivation reduced PD-L1 expression in HCC cells. Additionally, TCGA data and immunostaining analyses confirmed a positive correlation between the expression of hexokinase II (HK2), which plays a key role in glucose metabolism, and PD-L1. Notably, rapamycin treatment  decreased the expression of PD-L1 and HK2 in both high PD-L1-expressing HCC cells and sorafenib-resistant cells. Our results suggest that the modulation of PD-L1 expression by glucose deprivation may represent a strategy to overcome PD-L1 upregulation in patients with sorafenib-resistant HCC.

Impact of Exogenous Treatment with Histidine on Hepatocellular Carcinoma Cells.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib, a multi-kinase inhibitor, is the first-line therapy for advanced HCC. However, long-term exposure to sorafenib often results in reduced sensitivity and the development of resistance. Although various amino acids have been shown to contribute to cancer initiation and progression, little is known about the effects of histidine, a dietary essential amino acid that is partially taken up via histidine/large neutral amino acid transporter (LAT1), on cancer cells. In this study, we evaluated the effects of histidine on HCC cells and sensitivity to sorafenib. Remarkably, we found that exogenous histidine treatment induced a reduction in the expression of tumor markers related to glycolysis (GLUT1 and HK2), inflammation (STAT3), angiogenesis (VEGFB and VEGFC), and stem cells (CD133). In addition, LAT1 expression was downregulated in HCC tumor regions with high expression of GLUT1, CD133, and pSTAT3, which are known to induce sorafenib resistance. Finally, we demonstrated that combined treatment with sorafenib and histidine could be a novel therapeutic strategy to enhance the sensitivity to sorafenib, thereby improving long-term survival in HCC.