metabolism reprogramming

Follicular helper T (TFH) cells are essential for inducing germinal center (GC) reactions to mediate humoral adaptive immunity in tumors, but the mechanisms underlying TFH cell differentiation remain unclear. Here, we found that the metabolism sensor sirtuin 3 (SIRT3) is critical for TFH cell differentiation and GC formation during tumor and viral infection. SIRT3 deficiency in CD4+ T cells intrinsically enhanced TFH cell differentiation and GC reactions during tumor and virus infection. Mechanistically, damaged oxidative phosphorylation (OXPHOS) compensatively triggered the NAD+-glycolysis pathway to provide a cellular energy supply, which was necessary for SIRT3 deficiency-induced TFH cell differentiation...

Regulatory T cells (Tregs) play a crucial role in the homeostasis of the immune response. Tregs are mainly generated in the thymus and are characterized by the expression of Foxp3, which is considered the Treg master transcription factor. In addition, Tregs can be induced from naïve CD4+ T cells to express Foxp3 under specific conditions both in vivo (pTregs) and in vitro (iTregs). Both subsets tTregs and pTregs are necessary for the establishment of immune tolerance to self and non-self antigens. Although it has been postulated that iTregs may be less stable compared to tTregs, mainly due to epigenetic differences, accumulating evidence in animal models shows that iTregs are stable in vivo and could be used for the treatment of inflammatory disorders including autoimmune diseases and allogeneic transplant rejection...

Cullin RING E3 ligases (CRL) have emerged as key regulators of disease-modifying pathways and therapeutic targets. Cullin3 (Cul3)-containing CRL (CRL3) has been implicated in regulating hepatic insulin and oxidative stress signaling. However, CRL3 function in liver pathophysiology is poorly defined. Here, we report that hepatocyte Cul3 knockout results in rapid resolution of steatosis in obese mice. However, the remarkable resistance of hepatocyte Cul3 knockout mice to developing steatosis does not lead to overall metabolic improvement but causes systemic metabolic disturbances...

Human ornithine aminotransferase ( h OAT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme, has been shown to play an essential role in the metabolic reprogramming and progression of hepatocellular carcinoma (HCC). HCC accounts for approximately 75% of primary liver cancers and is within the top three causes of cancer death worldwide. As a result of treatment limitations, the overall 5-year survival rate for all patients with HCC is under 20%. The prevalence of HCC necessitates continued development of novel and effective treatment methods...

Inflammation and aberrant cellular metabolism are widely recognized as hallmarks of cancer. In pancreatic ductal adenocarcinoma (PDAC), inflammatory signaling and metabolic reprogramming are tightly interwoven, playing pivotal roles in the pathogenesis and progression of the disease. However, the regulatory functions of inflammatory mediators in metabolic reprogramming in pancreatic cancer have not been fully explored. Earlier, we demonstrated that pro-inflammatory mediator macrophage migration inhibitory factor (MIF) enhances disease progression by inhibiting its downstream transcriptional factor nuclear receptor subfamily 3 group C member 2 (NR3C2)...

The risk of cancer is higher in patients with asthma compared to those with allergic rhinitis for many types of cancer, except for certain cancers where a contrasting pattern is observed. This study offers a potential explanation for these observations, proposing that the premalignant levels of circulating transforming growth factor-β (TGF-β), IL-1β, and IL-6 as well as the reactivity of the TGF-β/Smad signaling pathway at the specific cancer site, are crucial factors contributing to the observed disparities...

Epithelial-to-mesenchymal transition (EMT) that endows cancer cells with increased invasive and migratory capacity enables cancer dissemination and metastasis. This process is tightly associated with metabolic reprogramming acquired for rewiring cell status and signaling pathways for survival in dietary insufficiency conditions. However, it remains largely unclear how transcription factor (TF)-mediated transcriptional programs are modulated during the EMT process. Here we reveal that depletion of a key epithelial TF, ELF3, triggers a TGFβ signaling activation-like mesenchymal transcriptomic profile and metastatic features linked to the aminoacyl-tRNA biogenesis pathway...

Ferroptosis is a distinct form of regulated cell death that is predominantly driven by the build-up of intracellular iron and lipid peroxides. Ferroptosis suppression is widely accepted to contribute to the pathogenesis of several tumours including prostate cancer. Results from some studies reported that prostate cancer cells can be highly susceptible to ferroptosis inducers, providing potential for an interesting new avenue of therapeutic intervention for advanced prostate cancer. In this Perspective, we describe novel molecular underpinnings and metabolic drivers of ferroptosis, analyse the functions and mechanisms of ferroptosis in tumours, and highlight prostate cancer-specific susceptibilities to ferroptosis by connecting ferroptosis pathways to the distinctive metabolic reprogramming of prostate cancer cells...

p16 is a tumor suppressor encoded by the CDKN2A gene whose expression is lost in ~50% of all human cancers. In its canonical role, p16 inhibits the G1-S phase cell cycle progression through suppression of cyclin dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway. However, the broader impact of p16/CDKN2A loss on other nucleotide metabolic pathways and potential therapeutic targets remains unexplored...

Just as the androgen receptor (AR), the estrogen receptor α (ERα) is expressed in the prostate and is thought to influence prostate cancer (PCa) biology. Yet, the incomplete understanding of ERα functions in PCa hinders our ability to fully comprehend its clinical relevance and restricts the repurposing of estrogen-targeted therapies for the treatment of this disease. Using two human PCa tissue microarray cohorts, we first demonstrated that nuclear ERα expression was heterogeneous among patients, being only detected in half of tumors...

PURPOSE: Metabolic reprogramming is currently considered a hallmark of tumor and immune development. It is obviously of interest to identify metabolic enzymes that are associated with clinical prognosis in head and neck squamous cell carcinomas (HNSCC). METHODS: Candidate genes were screened to construct folate metabolism scores by Cox regression analysis. Functional enrichment between high- and low-folate metabolism groups was explored by GO, KEGG, GSVA, and ssGSEA...

Recent studies have increasingly revealed the connection between metabolic reprogramming and tumor progression. However, the specific impact of metabolic reprogramming on inter-patient heterogeneity and prognosis in lung adenocarcinoma (LUAD) still requires further exploration. Here, we introduced a cellular hierarchy framework according to a malignant and metabolic gene set, named malignant & metabolism reprogramming (MMR), to reanalyze 178,739 single-cell reference profiles. Furthermore, we proposed a three-stage ensemble learning pipeline, aided by genetic algorithm (GA), for survival prediction across 9 LUAD cohorts (n = 2066)...

Glycolysis-related metabolic reprogramming is a central hallmark of human cancers, especially in renal cell carcinoma. However, the regulatory function of glycolytic signature in papillary RCC has not been well elucidated. In the present study, the glycolysis-immune predictive signature was constructed and validated using WGCNA, glycolysis-immune clustering analysis. PPI network of DEGs was constructed and visualized. Functional enrichments and patients' overall survival were analyzed. QRT-PCR experiments were performed to detect hub genes' expression and distribution, siRNA technology was used to silence targeted genes; cell proliferation and migration assays were applied to evaluate the biological function...

Transfer RNA (tRNA)-derived small RNAs (tsRNAs) are a new type of non-coding RNAs (ncRNAs) produced by the specific cleavage of precursor or mature tRNAs. tsRNAs are involved in various basic biological processes such as epigenetic, transcriptional, post-transcriptional, and translation regulation, thereby affecting the occurrence and development of various human diseases, including cancers. Recent studies have shown that tsRNAs play an important role in tumorigenesis by regulating biological behaviors such as malignant proliferation, invasion and metastasis, angiogenesis, immune response, tumor resistance, and tumor metabolism reprogramming...

Lipids are the key component of all membranes composed of a variety of molecules that transduce intracellular signaling and provide energy to the cells in the absence of nutrients. Alteration in lipid metabolism is a major factor for cancer heterogeneity and a newly identified cancer hallmark. Reprogramming of lipid metabolism affects the diverse cancer phenotypes, especially epithelial-mesenchymal transition (EMT). EMT activation is considered to be an essential step for tumor metastasis, which exhibits a crucial role in the biological processes including development, wound healing, and stem cell maintenance, and has been widely reported to contribute pathologically to cancer progression...

Cancer cells largely rely on aerobic glycolysis or the Warburg effect to generate essential biomolecules and energy for their rapid growth. The key modulators in glycolysis including glucose transporters and enzymes, e.g. hexokinase 2, enolase 1, pyruvate kinase M2, lactate dehydrogenase A, play indispensable roles in glucose uptake, glucose consumption, ATP generation, lactate production, etc. Transcriptional regulation and post-translational modifications (PTMs) of these critical modulators are important for signal transduction and metabolic reprogramming in the glycolytic pathway, which can provide energy advantages to cancer cell growth...

In response to an immune challenge, naive T cells undergo a transition from a quiescent to an activated state acquiring the effector function. Concurrently, these T cells reprogram cellular metabolism, which is regulated by iron. We and others have shown that iron homeostasis controls proliferation and mitochondrial function, but the underlying mechanisms are poorly understood. Given that iron derived from heme makes up a large portion of the cellular iron pool, we investigated iron homeostasis in T cells using mice with a T cell-specific deletion of the heme exporter, FLVCR1 [referred to as knockout (KO)]...

Despite progress in cancer immunotherapy, ovarian cancer (OC) prognosis continues to be disappointing. Recent studies have shed light on how not just tumour cells, but also the complex tumour microenvironment, contribute to this unfavourable outcome of OC immunotherapy. The complexities of the immune microenvironment categorize OC as a 'cold tumour'. Nonetheless, understanding the precise mechanisms through which the microenvironment influences the effectiveness of OC immunotherapy remains an ongoing scientific endeavour...

Clear cell renal cell carcinoma (ccRCC) is characterized by dysregulated hypoxia signaling and a tumor microenvironment (TME) highly enriched in myeloid and lymphoid cells. Loss of the von Hippel Lindau (VHL) gene is a critical early event in ccRCC pathogenesis and promotes stabilization of HIF. Whether VHL loss in cancer cells affects immune cells in the TME remains unclear. Using Vhl WT and Vhl-KO in vivo murine kidney cancer Renca models, we found that Vhl-KO tumors were more infiltrated by immune cells...

Cholesterol is crucial for cell survival and growth, and dysregulation of cholesterol homeostasis has been linked to the development of cancer. The tumor microenvironment (TME) facilitates tumor cell survival and growth, and crosstalk between cholesterol metabolism and the TME contributes to tumorigenesis and tumor progression. Targeting cholesterol metabolism has demonstrated significant antitumor effects in preclinical and clinical studies. In this review, we discuss the regulatory mechanisms of cholesterol homeostasis and the impact of its dysregulation on the hallmarks of cancer...