Cancer & Metabolism最新文献

Background: Obesity exacerbates the severity of cervical intraepithelial neoplasia (CIN), potentially through metabolic alterations. This study investigates how the Kisspeptin/GPR54 signaling pathway mediates mitochondrial energy metabolism in obesity-related CIN.

Methods: A clinical analysis of 980 samples was conducted to assess the correlation between Body Mass Index (BMI) and CIN grade. Transcriptomic analysis identified KISS1R as a key gene. Functional assays in cervical cancer (CC) cell lines, including CCK-8, wound healing, and Transwell assays, were used to evaluate the effects of KISS1 modulation. Mitochondrial function was assessed via oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) assays. A high-fat diet-induced CIN mouse model was used to investigate the in vivo effects.

Results: BMI positively correlated with CIN grade, with elevated KISS1R expression in higher CIN grades. Overexpression of KISS1 enhanced CC cell proliferation and migration by reprogramming mitochondrial energy metabolism. In high-fat environments, KISS1 silencing and mitochondrial activator PQQ modulated CC cell behavior. Activation of Kisspeptin/GPR54 in obese CIN mice exacerbated cervical lesions.

Conclusion: The Kisspeptin/GPR54 signaling pathway enhances mitochondrial energy metabolism, promoting obesity-related CIN grade. These findings provide a potential molecular mechanism linking obesity to CC and suggest new therapeutic targets.

Background: Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations represents a distinct subtype of leukemia. Emerging evidence suggests that regulation of redox metabolism contributes to tumorigenesis and reveals a metabolic vulnerability in anti-tumor therapies. However, the role of redox homeostasis between reactive oxygen species (ROS) and antioxidant systems plays in NPM1-mutated AML has not been fully elucidated.

Methods: First, ROS-related metabolic pathways in NPM1-mutated AML were analyzed using RNA-sequencing data. Intracellular and mitochondrial ROS levels in leukemia cells were detected using flow cytometry (FCM). The expression of nuclear factor (erythroid-derived 2)-like 2 (NRF2) was analyzed in public databases and further validated in AML primary blasts and cell lines by quantitative real-time PCR (qRT-PCR), western blotting, and immunofluorescence. Next, the mechanism underlying NRF2 expression was investigated through the RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP) and rescue experiments. Additionally, the downstream target gene of NRF2 was identified by bioinformatics analysis and chromatin immunoprecipitation (ChIP) assays. Furthermore, RNA interference and the NRF2 inhibitor ML385 were applied to explore the role of NRF2 in leukemia. Finally, the anti-leukemic effects of ML385 alone or in combination with the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax on AML cells were investigated using FCM analysis and western blotting, and further explored in cell line-derived xenograft (CDX) mouse models.

Results: In this study, we identified significant ROS accumulation in leukemia cells with NPM1 mutations. Meanwhile, elevated NRF2 expression and its nuclear localization were observed in NPM1-mutated AML cells. The high NRF2 expression levels were at least partially induced by fat mass and obesity-associated protein (FTO) via m⁶A modification. Functionally, NRF2 exerts its antioxidant effects by transcriptionally upregulating malic enzyme 1 (ME1) expression and enhancing its activity. Targeting NRF2/ME1 axis reduced NADPH/NADP⁺ ratio, increased ROS levels, impaired leukemia cell viability, and promoted apoptosis. More importantly, NRF2 inhibitor ML385 in combination with venetoclax showed synergistic anti-leukemic activity in vitro and in vivo.

Conclusion: Overall, our findings provide new insight into the therapeutic potential of targeting NRF2 and guide the development of innovative combination therapies in NPM1-mutated AML.

Background: Cells adapt to nutrient fluctuations through both signaling and epigenetic mechanisms. While amino acid (AA) deprivation is known to suppress protein synthesis via mTORC1 inactivation, the epigenetic pathways that support cellular adaptation and recovery remain poorly understood. We investigated how chromatin and transcriptional changes contribute to maintaining translational capacity during AA restriction and priming cells for growth upon AA repletion.

Methods: Human cells were cultured under amino acid-replete or -depleted conditions, and global histone methylation levels were assessed by Western blotting and ChIP-seq. RNA-seq and chromatin-associated RNA-seq (chromRNA-seq) were used to evaluate gene expression and transcriptional output. Ribosome profiling and [³⁵S]-methionine/cysteine or O-propargyl-puromycin (OPP) incorporation assays measured protein synthesis. Functional contributions of SETD8 and MYC were tested through knockdown and overexpression experiments.

Results: AA deprivation induced a selective, genome-wide loss of H4K20me1, particularly from gene bodies, and led to increased MYC expression and binding at promoter regions. These changes were most pronounced at genes encoding ribosomal proteins and translation initiation factors. Although overall protein synthesis declined during AA restriction, these cells showed increased translational capacity evidenced by accumulation of monomeric ribosomes and enhanced translation upon AA repletion. Loss of H4K20me1 was independent of mTORC1 signaling and partly driven by SETD8 protein downregulation. While MYC overexpression alone was insufficient to upregulate translation-related genes, its combination with SETD8 knockdown in nutrient-rich conditions was both necessary and sufficient to induce expression of these genes and enhance protein synthesis.

Conclusions: Our findings reveal a chromatin-based mechanism by which cells integrate metabolic status with transcriptional regulation to adapt to amino acid limitation. Loss of H4K20me1 and increased MYC activity act in parallel to prime the translational machinery during AA deprivation, enabling rapid recovery of protein synthesis upon nutrient restoration. This mechanism may help explain how cells maintain competitive growth potential under fluctuating nutrient conditions and has implications for understanding MYC-driven cancer progression.

Background: Colon cancer is strongly influenced by lifestyle factors. Sociodemographic factors like sex and socioeconomic position (SEP) might modulate the relationship between lifestyle and colon cancer risk. Metabolomics offers potential to uncover biological mechanisms linking lifestyle and colon cancer.

Methods: Lifestyle and untargeted metabolomic data were available from a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC), including 1,067 colon cancer cases and 1,067 controls matched on age, sex, study centre, and blood collection time. Serum samples were analyzed using liquid chromatography-mass spectrometry. The Healthy Lifestyle Index (HLI) score was derived from smoking habits, alcohol intake, body mass index (BMI), physical activity, and diet. Penalised regression was applied in controls to derive metabolic signatures for the HLI and the lifestyle components. Associations of lifestyle factors and the metabolic signatures with colon cancer risk were estimated in conditional logistic regression models, overall and by sex and SEP.

Results: The HLI score was inversely associated with colon cancer risk, with an odds ratio (OR) per 1-standard deviation (SD) increment equal to 0.79; 95% CI: 0.71, 0.87. The metabolic signature of HLI, comprising 130 features, was moderately correlated with HLI (r = 0.59; 94% CI: 0.56, 0.61), and was inversely associated with colon cancer risk (OR = 0.86; 95% CI: 0.78, 0.95). After adjustment for the HLI score, the association of the metabolic signature of HLI and colon cancer risk was null (OR = 1.00, 95% CI 0.88, 1.13). Associations of lifestyle factors and the metabolic signature with colon cancer risk were consistently stronger for men than for women and did not differ by SEP.

Conclusions: In this study across seven European countries, healthy lifestyle was inversely associated with colon cancer risk, with stronger associations in men than women and no differences across SEP. However, the serum metabolic signatures after adjustment for lifestyle factors were not found to be associated with colon cancer risk, suggesting that lifestyle impacts colon cancer through mechanisms not captured by the signatures.

Background: Targeted therapy interventions using tyrosine kinase inhibitors (TKIs) provide encouraging treatment responses in patients with ALK-rearranged lung adenocarcinomas, yet resistance occurs almost inevitably. In addition to tumor cell-intrinsic resistance mechanisms, accumulating evidence suggests that cancer-associated fibroblasts (CAFs) within the tumor microenvironment contribute to therapy resistance. This study aimed to investigate CAF-driven molecular networks that shape the therapeutic susceptibility of ALK-driven lung adenocarcinoma cells.

Methods: Three-dimensional (3D) spheroid co-cultures comprising ALK-rearranged lung adenocarcinoma cells and CAFs were utilized to model the tumor microenvironment. Single-cell RNA sequencing was performed to uncover transcriptional differences between TKI-treated homotypic and heterotypic spheroids. Functional assays assessed the effects of CAF-conditioned medium and CAF-secreted factors on tumor cell survival, proliferation, lipid metabolism, and downstream AKT signaling. The therapeutic potential of targeting metabolic vulnerabilities was evaluated using pharmacological inhibition of lipid metabolism and by ferroptosis induction.

Results: CAFs significantly diminished the apoptotic response of lung tumor cells to ALK inhibitors while simultaneously enhancing their proliferative capacity. Single-cell RNA sequencing identified lipogenesis-associated genes as a key transcriptional difference between TKI-treated homotypic and heterotypic lung tumor spheroids. CAF-conditioned medium and the CAF-secreted factors HGF and NRG1 activated AKT signaling in 3D-cultured ALK-rearranged lung tumor cells, leading to increased de novo lipogenesis and suppression of lipid peroxidation. These metabolic adaptations were critical for promoting tumor cell survival and fostering therapy resistance. Notably, both dual inhibition of ALK and the lipid-regulatory factor SREBP-1, as well as co-treatment with ferroptosis inducers such as erastin or RSL3, effectively disrupted the CAF-driven metabolic-supportive niche and restored sensitivity of resistant lung tumor spheroids to ALK inhibition.

Conclusions: This study highlights a critical role for CAFs in mediating resistance to ALK-TKIs by reprogramming lipid metabolism in ALK-rearranged lung cancer cells. It suggests that targeting these metabolic vulnerabilities, particularly through inhibition of lipid metabolism or induction of ferroptosis, could provide a novel therapeutic approach to overcome resistance and improve patient outcomes.

Background: Despite decades of efforts to find successful treatment approaches, cachexia remains a major unmet medical need. This condition, that affects patients with diverse underlying conditions, is characterized by severe muscle loss and is associated with reduced quality of life and limited survival. Search for underlying mechanisms that may guide cachexia treatment has mainly evolved around potential atrophy-inducing roles of inflammatory mediators, and in cancer patients, tumor-derived factors. Recently, a new paradigm emerged as it is becoming evident that specific immune cells inhabit atrophic muscle tissue. Arginase 1 (Arg1) expression is characteristic of these immune cells. Studies of potential contributions of these immune cells to loss of muscle mass and function is in its infancy, and the contribution of ARG1 to these processes remains elusive.

Methods: Analyses of RNA sequencing data from murine cachexia models and comprehensive, unbiased open approach proteomics analyses of skeletal myotubes was performed. In vitro techniques were employed to evaluate mitochondrial function and capacity in skeletal muscle cells and cardiomyocytes. Functional bioassays were used to measure autophagy activity. ARG1 level in patients' plasma was evaluated using ELISA, and the association between ARG1 level and patient survival, across multiple types of cancer, was examined using the online database Kaplan-Meier plotter.

Results: In line with arginine-degrading activity of ARG1, we found signs of arginine restriction in atrophic muscles. In response to arginine restriction, mitochondrial functions and ATP generation was severely compromised in both skeletal muscle cells and in cardiomyocytes. In skeletal muscle cells, arginine restriction enhanced the expression of autophagic proteins, suggesting autophagic degradation of cellular content. Reduction in mitochondria marker TIMM23 supports selective autophagic degradation of mitochondria (mitophagy). In arginine starved cardiomyocytes, mitochondrial dysfunction is accompanied by both increased bulk autophagy and mitophagy. In cancer patients, we found an association between ARG1 expression and accelerated weight loss and reduced survival, further supporting a role of ARG1-producing cells in cachexia pathogenesis.

Conclusion: Together, our findings point to a mechanism for cachexia which depends on expansion of ARG1-expressing myeloid cells, local restriction of arginine, loss of mitochondrial capacity and induced catabolism in skeletal muscle cells and in the heart.

Breast cancer remains the most prevalent malignancy among women globally, with its complexity linked to genetic variations and metabolic alterations within tumor cells. This study investigates the role of fumarate hydratase (FH), a key enzyme in the tricarboxylic acid (TCA) cycle, in breast cancer progression. Our findings reveal that FH mRNA and protein levels are significantly upregulated in breast cancer tissues and correlate with poor patient prognosis and aggressive tumor characteristics. Using in vitro and in vivo models, we demonstrate that FH overexpression enhances breast cancer cell proliferation, migration, and invasion through metabolic reprogramming and by increasing reactive oxygen species (ROS) production. Furthermore, we identify matrix metalloproteinase 1 (MMP1) as a downstream effector of FH, linked to p21 downregulation, elucidating a novel regulatory pathway influencing tumor behavior. Interestingly, unlike its tumor-suppressing role in other cancer types, this study highlights FH's oncogenic potential in breast cancer. Our results suggest that FH enhances cancer cell viability and aggressiveness via both catalytic and non-catalytic mechanisms. This work not only underscores the metabolic adaptations of breast cancer cells but also proposes FH as a potential biomarker and therapeutic target for breast cancer management.

Increasing emphasis has been placed on improving the physiological relevance of cell culture media with formulations such as Human Plasma-Like Medium (HPLM). Given that shifts in mitochondrial metabolism and nutrient use are emerging as anti-cancer targets, the present study sought to investigate the impact of culture media formulation on mitochondrial bioenergetics and cancer cell growth. To do this, we used acute myeloid leukemia (AML) cells and compared acute and chronic effects of HPLM versus different supraphysiological medias. The AML mitochondrial phenotype was largely unaffected by exposure to either physiological or supraphysiological medias, establishing that the key features of AML mitochondria remain phenotypically stable under diverse nutrient conditions and proliferation rates. Both acute and chronic culturing in HPLM slowed AML cell proliferation. However, merely identifying and supplementing single nutrients that were deficient in HPLM did not improve proliferation and was not sufficient to pinpoint actionable fuel preferences. Transferring cells back to native Iscove's Modified Dulbecco's Medium (IMDM) media immediately restored the proliferative phenotype, suggesting responsiveness to the entirety of the nutrient environment. Supraphysiological culture medias other than IMDM were all characterized by slower proliferation; however, none were associated with changes in cell viability, demonstrating that the native culture medium is optimal if the experimental aim is maximal growth. Despite Dulbecco's Modified Eagle Medium (DMEM) being similar in nutrient composition to IMDM and categorized as supraphysiological, both acute and chronic culturing in DMEM resulted in slower growth, akin to what was observed with HPLM. Altogether, independent of growth, AML mitochondria remain largely unperturbed by changes in the culture media, and rather than specific nutrients or physiological relevance, AML cell proliferation is influenced by the complete nutrient profile.

Background: The tumor microenvironment (TME) supplies critical metabolites that support cancer cell survival and progression. Adipocytes support tumor progression by secreting free fatty acids (FFAs) and adipokines; however, the role and mechanisms underlying lipid droplet (LD) release from adipocytes remain elusive.

Methods: Using two nasopharyngeal carcinoma (NPC) cell lines and primary human pre-adipocytes (HPA), we evaluate the effect of LDs on cell growth, proliferation, colony formation, and migration. We also assess the roles of LD on the tumor progression in vivo. Using RNA-seq analysis, we elucidate the effect of hypoxic NPC cell-derived exosomes (H-exo) on the gene expression profile of adipocytes. By co-culture system, we investigated the effect of vacuolar protein sorting 4 homolog B (VPS4B)-annexin A5 (ANXA5) interaction on adipocyte LD maturity and release.

Results: Herein, we report that LDs, rather than FFAs, are the primary lipid form transferred from adipocytes to NPC cells, enhancing cancer progression. NPC cells internalize LDs directly via macropinocytosis, while H-exo induces oxidative stress and membrane fluidity in adipocytes, leading to LD release. Transcriptomic and proteomic analyses reveal that VPS4B triggers LD release by interacting with ANXA5, and low LKB1 in H-exo enhances VPS4B O-linked N-acetylglucosamine (O-GlcNAc) modification through the inhibition of serine/threonine kinase 11 (STK11/LKB1)-AMP-activated protein kinase (AMPK) pathway and activation of the hexosamine biosynthesis pathway (HBP) flux.

Conclusions: This study uncovers critical mechanisms of LD transfer in the TME, suggesting new therapeutic avenues in NPC.