bims-glucam 2022-07-10 papers

Biochem Pharmacol. 2022 Jun 30. pii: S0006-2952(22)00253-2. [Epub ahead of print]202 115159

Trabectedin suppresses escape from therapy-induced senescence in tumor cells by interfering with glutamine metabolism.

Francesco Pacifico, Stefano Mellone, Maurizio D'Incalci, Mariano Stornaiuolo, Antonio Leonardi, Elvira Crescenzi.

Conventional and targeted cancer therapies may induce a cellular senescence program termed therapy-induced senescence. However, unlike normal cells, cancer cells are able to evade the senescence cell cycle arrest and to resume proliferation, driving tumor recurrence after treatments. Cells that escape from therapy-induced senescence are characterized by a plastic, cancer stem cell-like phenotype, and recent studies are beginning to define their unique metabolic features, such as glutamine dependence. Here, we show that the antineoplastic drug trabectedin suppresses escape from therapy-induced senescence in all cell lines studied, and reduces breast cancer stem-like cells, at concentrations that do not affect the viability of senescent tumor cells. We demonstrate that trabectedin downregulates both the glutamine transporter SLC1A5 and glutamine synthetase, thereby interfering with glutamine metabolism. On the whole, our results indicate that trabectedin targets a glutamine-dependent cancer stem-like cell population involved in evasion from therapy-induced senescence and suggest a therapeutic potential for trabectedin combined with pro-senescence chemotherapy in tumor treatment.

Keywords: Escape; Glutamine; Glutamine synthetase; SLC1A5; Therapy-induced senescence; Trabectedin

DOI: https://doi.org/10.1016/j.bcp.2022.115159

Cancer Lett. 2022 Jul 04. pii: S0304-3835(22)00299-3. [Epub ahead of print] 215815

N6-methyladenosine modification and metabolic reprogramming of digestive system malignancies.

Xianlei Cai, Chao Liang, Miaozun Zhang, Yuan Xu, Yihui Weng, Xueying Li, Weiming Yu.

N6-methyladenosine (m6A) is a eukaryotic post-transcriptional modification involved in cell growth and developmental processes, including RNA transcription, alternative splicing, degradation, and translation. It is also involved in the development of various cancers. Metabolic reprogramming enables cancer cells to obtain nutrition from the tumor microenvironment, which is a hallmark of cancer. Numerous studies have shown that m6A modification induces metabolic reprogramming in cancer by regulating the expression of metabolic core genes or activation of metabolic signaling pathways. Digestive system malignancies include esophageal, gastric, colorectal, liver, pancreatic, and other cancers, all of which are associated with poor outcomes. This review summarizes the role of m6A modification in the metabolic reprogramming of digestive system malignancies, with the aim of identifying therapeutic strategies.

Keywords: Epigenetic modification; Glucose metabolism; Glutamine metabolism; Lipid metabolism

DOI: https://doi.org/10.1016/j.canlet.2022.215815

Hemasphere. 2022 Jul;6(7): e740

Metabolic Regulation of Hematopoietic Stem Cells.

Claudia Morganti, Nina Cabezas-Wallscheid, Keisuke Ito.

Cellular metabolism is a key regulator of hematopoietic stem cell (HSC) maintenance. HSCs rely on anaerobic glycolysis for energy production to minimize the production of reactive oxygen species and shift toward mitochondrial oxidative phosphorylation upon differentiation. However, increasing evidence has shown that HSCs still maintain a certain level of mitochondrial activity in quiescence, and exhibit high mitochondrial membrane potential, which both support proper HSC function. Since glycolysis and the tricarboxylic acid (TCA) cycle are not directly connected in HSCs, other nutrient pathways, such as amino acid and fatty acid metabolism, generate acetyl-CoA and provide it to the TCA cycle. In this review, we discuss recent insights into the regulatory roles of cellular metabolism in HSCs. Understanding the metabolic requirements of healthy HSCs is of critical importance to the development of new therapies for hematological disorders.

DOI: https://doi.org/10.1097/HS9.0000000000000740