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A new approach helps examine the proportion of cancerous and healthy stem cells in patients with chronic myeloid leukemia and how this influences treatment outcomes.A new approach helps examine the proportion of cancerous and healthy stem cells in patients with chronic myeloid leukemia and how this influences treatment outcomes.

Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans -vaccenic acid (TVA) directly promotes effector CD8 + T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans -fatty acids enriched in human milk, but the human body cannot produce TVA endogenously 1 . Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter 2 , 3 , but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively 4 , 5 . Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands 6 – 8 . TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP–PKA–CREB axis for enhanced CD8 + T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8 + T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours. A screen of nutrient-derived compounds identified trans -vaccenic acid as a promoter of effector T cell function, and functional assays demonstrate that this occurs via inactivation of GPR43 on T cells.

Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies. Copper is a transition metal ion essential for the regulation of cellular oxidative stress and ATP production. Now, the inhibition of copper-trafficking proteins by a small molecule has been shown to significantly reduce proliferation of cancer cells. The results indicate that copper-trafficking proteins could represent new anti-tumour therapeutic targets.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer and frequently metastasizes to LNs. Identifying metastasis-promoting factors is of immense clinical interest, as the prognosis for patients with even a single unilateral LN metastasis is extremely poor. Here, we report that p90 ribosomal S6 kinase 2 (RSK2) promotes human HNSCC cell invasion and metastasis. We determined that RSK2 was overexpressed and activated in highly invasive HNSCC cell lines compared with poorly invasive cell lines. Expression of RSK2 also correlated with metastatic progression in patients with HNSCC. Ectopic expression of RSK2 substantially enhanced the invasive capacity of HNSCC cells, while inhibition of RSK2 activity led to marked attenuation of invasion in vitro. Additionally, shRNA knockdown of RSK2 substantially reduced the invasive and metastatic potential of HNSCC cells in vitro and in vivo in a xenograft mouse model, respectively. Mechanistically, we determined that cAMP-responsive element-binding protein (CREB) and Hsp27 are phosphorylated and activated by RSK2 and are important for the RSK2-mediated invasive ability of HNSCC cells. Our findings suggest that RSK2 is involved in the prometastatic programming of HNSCC cells, through phosphorylation of proteins in a putative signaling network. Moreover, targeting RSK2 markedly attenuates in vitro invasion and in vivo metastasis of HNSCC cells, suggesting that RSK2 may represent a therapeutic target in the treatment of metastatic HNSCC.

Both PU.1 (also called SFPI1), an Ets-family transcription factor, and AML1 (also called RUNX1), a DNA-binding subunit of the CBF transcription factor family, are crucial for the generation of all hematopoietic lineages, and both act as tumor suppressors in leukemia. An upstream regulatory element (URE) of PU.1 has both enhancer and repressor activity and tightly regulates PU.1 expression. Here we show that AML1 binds to functionally important sites within the PU.1 upstream regulatory element and regulates PU.1 expression at both embryonic and adult stages of development. Analysis of mice carrying conditional AML1 knockout alleles and knock-in mice carrying mutations in all three AML1 sites of the URE proximal region demonstrated that AML1 regulates PU.1 both positively and negatively in a lineage dependent manner. Dysregulation of PU.1 expression contributed to each of the phenotypes observed in these mice, and restoration of proper PU.1 expression rescued or partially rescued each phenotype. Thus, our data demonstrate that PU.1 is a major downstream target gene of AML1.

This manuscript of research highlight focused on one paper recently published in Nature Metabolism entitled “Mitochondrial Long Non‐coding RNA GAS5 Tunes TCA Metabolism in Response to Nutrient Stress” from Lin Aifu's group in Zhejiang University. In this manuscript, we discussed the novel findings in Lin's paper and concluded that the metabolon is emerging as a novel cellular structure that regulates specific metabolic pathways.

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1–AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target. Chen and colleagues report that the third enzyme in the oxidative pentose phosphate pathway (PPP), 6PGD, controls cancer cell proliferation by regulating LKB1–AMPK signalling. Inhibitors of 6PGD decrease tumorigenesis in mouse xenografts.

How oncogenic signalling coordinates glycolysis and anabolic biosynthesis in cancer cells remains unclear. We recently reported that the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) regulates anabolic biosynthesis by controlling intracellular levels of its substrate 3-phosphoglycerate and product 2-phosphoglycerate. Here we report a novel mechanism in which Y26 phosphorylation enhances PGAM1 activation through release of inhibitory E19 that blocks the active site, stabilising cofactor 2,3-bisphosphoglycerate binding and H11 phosphorylation. We also report the crystal structure of H11-phosphorylated PGAM1 and find that phospho-H11 activates PGAM1 at least in part by promoting substrate 3-phosphoglycerate binding. Moreover, Y26 phosphorylation of PGAM1 is common in human cancer cells and contributes to regulation of 3-phosphoglycerate and 2-phosphoglycerate levels, promoting cancer cell proliferation and tumour growth. As PGAM1 is a negative transcriptional target of TP53 , and is therefore commonly upregulated in human cancers, these findings suggest that Y26 phosphorylation represents an additional acute mechanism underlying phosphoglycerate mutase 1 upregulation. Tumour cells may undergo a dramatic metabolic shift in which glycolysis is favoured despite the presence of oxygen. By solving its crystal structure, Hitosugi et al . reveal how phosphorylation of the enzyme phosphoglycerate mutase 1 regulates glycolytic flux in cancer cells.

The oxidative pentose phosphate pathway (PPP) is crucial for cancer cell metabolism and tumor growth. We recently reported that targeting a key oxidative PPP enzyme, 6-phosphogluconate dehydrogenase (6PGD), using our novel small molecule 6PGD inhibitors Physcion and its derivative S3, shows anti-cancer effects. Notably, humans with genetic deficiency of either 6PGD or another oxidative PPP enzyme, glucose-6-phosphate dehydrogenase (G6PD), exhibit non-immune hemolytic anemia upon exposure to aspirin and various anti-malarial drugs. Inspired by these clinical observations, we examined the anti-cancer potential of combined treatment with 6PGD inhibitors and anti-malarial drugs. We found that stable knockdown of 6PGD sensitizes leukemia cells to anti-malarial agent dihydroartemisinin (DHA). Combined treatment with DHA and Physcion activates AMP-activated protein kinase, leading to synergistic inhibition of human leukemia cell viability. Moreover, our combined therapy synergistically attenuates tumor growth in xenograft nude mice injected with human K562 leukemia cells and cell viability of primary leukemia cells from human patients, but shows minimal toxicity to normal hematopoietic cells in mice as well as red blood cells and mononucleocytes from healthy human donors. Our findings reveal the potential for combined therapy using optimized doses of Physcion and DHA as a novel anti-leukemia treatment without inducing hemolysis.

Constitutively activated tyrosine kinases are frequently implicated in the pathogenesis of human leukemia, making them attractive therapeutic targets. Though tyrosine kinase inhibitors have proven remarkably effective for leukemia treatment, they are disease-remitting rather than curative, and many patients develop overt resistance during therapy. This underscores the importance of designing alternate and/or complementary anti-leukemia therapeutic strategies. Our phospho-proteomics studies revealed that serine/threonine kinase p90RSK2 (RSK2) is a common substrate of distinct leukemogenic tyrosine kinases including BCR-ABL and FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD). We found that RSK2 is dispensable for BCR-ABL-induced myeloproliferative neoplasm, but required for FLT3-ITD-induced myeloid transformation in a murine bone marrow transplant assay. Moreover, inhibition of RSK2 by selective RSK inhibitor fmk induces significant apoptosis in FLT3-ITD- positive, but not BCR-ABL expressing leukemia cell lines and primary leukemia cells from human patients. These results suggest that RSK2 may represent an alternative therapeutic target in the treatment of FLT3-ITD-positive leukemia. Our phospho- proteomics studies also revealed a group of metabolic enzymes as tyrosine phosphorylated in leukemia cells transformed by different leukemogenic tyrosine kinases. Among those identified, we found that glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) is important for the coordination of bioenergetic and anabolic biosynthetic pathways in leukemia cells, which is essential for cell proliferation and disease development. We developed a selective PGAM1 inhibitor, PGMI-004A, that effectively inhibits viability of diverse leukemia cell lines and primary leukemia cells from patients with no off-target activity and minimal toxicity. Additionally, we found that 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP) is commonly upregulated by lysine acetylation in cancer/leukemia cells. 6PGD provides an additional link between the oxidative PPP and lipogenesis through 6PGD product-dependent inhibition of LKB1-AMPK signaling, and represents a novel anti-cancer/leukemia target. We developed selective small molecule 6PGD inhibitors, Physcion and S3, and found that treatment with 6PGD inhibitors alone or in combination with anti-malarial drug dihydroartemisinin effectively inhibits cell viability in leukemia cell lines and patient samples, and attenuates leukemia cell-derived tumor growth in mice with minimal off-target toxicity. Collectively, these studies provide gproof of principleh for the development of RSK2, PGAM1 and 6PGD inhibitors as novel anti-leukemia agents.