Cancer & Metabolism最新文献

Background: L-type amino acid transporter 1 (LAT1; SLC7A5), which preferentially transports large neutral amino acids (LNAAs), is highly upregulated in various cancers and represents a promising therapeutic target. The first-in-class LAT1-specific inhibitor, nanvuranlat (JPH203, KYT-0353), has exhibited potent anti-cancer effects and is under clinical evaluation. However, alterations in the amino acid availability in cancer cells underlying its pharmacological activities remain to be elucidated.

Methods: Amino acids in nanvuranlat-treated cancer cells were measured by high-performance liquid chromatography. LAT1 knockdown was performed using siRNA. To mimic LAT1 inhibition, cancer cells were incubated in culture media lacking specific LNAA(s) reduced by nanvuranlat. The consequences of these treatments were compared by cell-based assays, including analyses of amino acid contents, cell growth, amino acid-related signaling pathways, cell cycle, ATP production rate, and transcriptomes by RNA sequencing. Metabolome of nanvuranlat-treated and untreated cells was compared by mass spectrometry. The effects of nanvuranlat on amino acid composition were also examined in three-dimensional cancer cell spheroids.

Results: Both pharmacological and genetic inhibition of LAT1 preferentially and continuously reduced valine, isoleucine, and tryptophan in pancreatic cancer MIA PaCa-2 cells. Nanvuranlat induced similar alterations in intracellular amino acids in multiple cancer cell lines. Depletion of these amino acids from culture media selectively lowered their intracellular concentrations, recapitulating the effects of nanvuranlat on cell growth, amino acid-related mTORC1/GAAC signaling pathways, and cell cycle. Deprivation of valine or isoleucine exhibited more pronounced impacts than tryptophan in all assays. As a novel pharmacological action of nanvuranlat mediated by the reductions in valine and isoleucine, we revealed downregulation of multiple genes in the TCA cycle and respiratory chain, accompanied by a decreased mitochondrial ATP production rate. Consistently, metabolomics revealed broad decreases in the TCA cycle intermediates by LAT1 inhibition. Nanvuranlat also similarly influenced the amino acid levels in cancer cell spheroids.

Conclusions: Reductions in valine and isoleucine in cancer cells primarily account for the multifaceted anti-cancer pharmacological activities of LAT1 inhibition by nanvuranlat. This study establishes the molecular basis for LAT1-targeted therapy and highlights growth-promoting processes in cancer cells that can be exploited pharmacologically by modulating the availability of specific amino acids.

Colorectal cancer (CRC) is a globally prevalent malignancy that poses a substantial threat to human health. Despite advancements in prevention, diagnosis, and treatment, CRC remains a formidable clinical challenge due to the incomplete elucidation of its pathological mechanisms. Glutamine, an abundant amino acid, exerts pivotal roles in energy production, redox homeostasis, macromolecular biosynthesis, and signal transduction within cancer cells. Elucidating the role of glutamine in CRC pathogenesis is therefore of profound significance. In this study, we investigated the regulatory role of Cyclin-dependent kinase 5 (Cdk5) in glutamine metabolism in CRC, employing both human CRC cell models and murine models. Our findings demonstrated that Cdk5 knockdown accelerated glutamine uptake while suppressing the proliferation of CRC cells. Further exploration of the underlying molecular mechanisms revealed that Cdk5 physically interacts with EZH2. Besides, Cdk5 phosphorylates EZH2 at specific sites, and then the PRC2 complex (centered around EZH2) catalyzes the production of H3K27me3, an inhibitory marker, to regulate the expression of genes involved in glutamine metabolism. At the same time, we also found that modulation of the Cdk5-EZH2 axis alters the epigenetic landscape of genes associated with glutamine transporters and tricarboxylic acid cycle (TCA) enzymes, resulting in reduced mitochondrial activity, impaired glutamine utilization in the TCA cycle, and decreased ATP production-collectively impacting the global glutamine metabolic processes in CRC cells. In in vivo experiments utilizing a murine CRC model, we established five experimental groups. Results showed that Dinaciclib treatment suppressed tumor growth in the CRC model, with this inhibitory effect being further potentiated upon combination with glutamine deprivation. These findings not only uncover the intricate interplay between Cdk5, EZH2, and glutamine metabolism in CRC but also offer novel insights into the pathogenic mechanisms of CRC and identify potential therapeutic targets.

Background: Colorectal cancer (CRC) is among the most prevalent malignant tumors, with liver metastasis as the leading cause of mortality. Although metabolic reprogramming is known to play a crucial role in tumor metastasis, our understanding of this process during colorectal cancer liver metastasis (CRLM) remains limited.

Methods: A stepwise mouse model of CRC liver metastasis was developed, and metabolomic profiling was performed to verify model stability and identify metabolic changes. Single-cell RNA sequencing (scRNA-seq) was used to assess oxidative phosphorylation (OXPHOS) activity within the metastatic tumor microenvironment (TME). Additionally, spatial transcriptomics (ST) was conducted to elucidate the spatial distribution of metabolic phenotypes within metastatic sites. Finally, in vivo experiments were conducted by administering TGFβ inhibitor (LY2157299) or OXPHOS inhibitor (IACS-010759) to evaluate the potential for liver metastasis, and in vitro, the functions of HCT116 and SW620 cells were assessed through Transwell assays and oxygen consumption rate (OCR) measurements.

Results: Metabolomic profiling revealed heightened tricarboxylic acid (TCA) cycle activity in liver metastases. ScRNA-seq analysis showed increased OXPHOS in metastatic cells, including a highly malignant cell subtype characterized by augmented OXPHOS. Further analysis identified a significant upregulation of OXPHOS associated with TGFβ pathway activation. ST localized this OXPHOS -enriched subtype within metastatic tissue. Both in vivo and in vitro experiments demonstrate that inhibition of TGFβ signaling reduces OXPHOS activity, thereby attenuating the progression of colorectal cancer liver metastasis.

Conclusions: This study identifies OXPHOS upregulation as a key metabolic alteration during CRC liver metastasis, which could be induced by TGFβ signaling pathway. These findings contribute to a refined understanding of CRC metabolic adaptation in liver metastases and may inform therapeutic strategies targeting OXPHOS in advanced CRC.