Cancer & Metabolism最新文献

Obesity is an established risk factor for breast cancer (BC), yet the specific mechanisms driving this association remain unclear. Dysregulated lipid metabolism has emerged as a key factor in cancer cell biology, and, while obesity is often accompanied by hyperlipidemia, the isolated impact of elevated lipid levels on BC growth has not been experimentally tested. Using the E0771 and Py230 orthotopic models of obesity-accelerated BC growth in immune-competent mice, we investigated the role of systemic lipids on tumor growth. Combining dietary and genetic mouse models, we show that elevated circulating lipids are sufficient to accelerate BC tumor growth even in the absence of obesity or alterations in blood glucose and/or insulin levels. Pharmacological lowering of systemic lipid levels attenuates BC growth in obese mice, suggesting a direct role for lipids in fueling tumor expansion. Notably, we also show that weight loss alone, without a corresponding reduction in lipid levels such as that induced by a ketogenic diet, fails to protect against BC, highlighting the necessity of targeting lipid metabolism in obesity-associated BC. Our findings establish hyperlipidemia as a critical driver of BC progression and suggest that lipid-lowering interventions may be a promising strategy to mitigate BC risk in individuals with obesity.

Background: Lipid homeostasis is critical for pancreatic adenocarcinoma (PDAC) cell survival under hypoxic and nutrient-deprived conditions. Hypoxia inhibits unsaturated lipid biosynthesis, compelling cancer cells to depend on exogenous unsaturated lipids to counteract saturated lipid-induced toxicity. Our previous work revealed that cancer-associated fibroblasts (CAFs) secrete unsaturated lipids, primarily lysophosphatidylcholines (LPCs), to alleviate lipotoxic stress in PDAC cells. Here, we conducted a drug screen to identify compounds that bypass the rescue effect of exogenous LPCs on cancer cell survival under stress.

Methods: We employed high-throughput screening of a bioactive chemical library with 3,336 compounds, including FDA-approved drugs and drug-like molecules against defined molecular targets. Two assays were performed: a cytotoxicity assay to exclude indiscriminately toxic compounds at 1 μM and an LPC crosstalk inhibition assay to identify compounds that selectively reduce cancer cell viability in the presence of LPCs under stress conditions.

Results: CB-839, a glutaminase inhibitor, was identified as the most effective compound, selectively inhibiting the LPC-mediated rescue of PDAC cell viability effect without intrinsic cytotoxicity. Mechanistic studies revealed that CB-839 induces cell death by activating the pro-apoptotic ATF4/CHOP pathway, reducing antioxidant production, and increasing reactive oxygen species (ROS). While CB-839 showed limited efficacy against PDAC tumor cells alone in vivo, it modestly inhibited tumor growth in a PDAC-CAF co-implanted subcutaneous mouse model, highlighting its potential to disrupt CAF-mediated nutrient support. Additionally, glutamine antagonists showed more potent tumor-suppressive effects than CB-839.

Conclusion: Our findings emphasize the importance of glutamine metabolism inhibition in suppressing tumor growth and disrupting CAF-mediated crosstalk. We further underscore the potential of glutamine antagonist prodrugs as a strategy to target metabolic vulnerabilities in PDAC.

Purpose: Cancer cells rely on serine biosynthesis for growth, but its regulation in colorectal cancer (CRC) remains not well understood. This study identifies the m⁵C methyltransferase NSUN2 (NOP2/Sun domain family, member 2) as a key regulator of serine biosynthesis, revealing a novel mechanism driving CRC progression.

Methods: The expression and prognostic value of NSUN2 were evaluated using bioinformatics analyses and immunohistochemistry (IHC) assays. The effects of NSUN2 on cellular serine biosynthesis, intracellular reactive oxygen species (ROS) levels, and apoptosis levels were analyzed both in vitro and in vivo. Additionally, RNA sequencing, Methylated RNA Immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP), and RNA stability assays were utilized to screen and validate the association between NSUN2 and phosphoglycerate dehydrogenase (PHGDH).

Results: NSUN2 was found to be highly expressed in CRC and associated with poor patient survival. PHGDH, a direct downstream target of NSUN2, plays a crucial role in NSUN2-mediated serine biosynthesis. Furthermore, inhibition of NSUN2 significantly reduced the intracellular NADH/NAD⁺ and NADPH/NADP⁺ ratios, leading to an increase in ROS levels and apoptosis levels, thereby inhibiting CRC progression. Additionally, NSUN2 enhances PHGDH expression and mRNA stability by binding to the "reader" protein m⁵C-Aly/REF export factor (ALYREF).

Conclusions: This study identified a novel NSUN2/ALYREF/m⁵C-PHGDH axis might be promising therapeutic targets for CRC.

Background: Acute myeloid leukemia (AML) is a devastating hematological malignancy with limited therapeutic options and poor survival outcomes. Therefore, the development of novel and selective anti-AML therapies is needed. 6-methoxydihydroavicine (6ME), a benzophenanthridine alkaloid, imparted selective AML cell death in vitro and in vivo. Mechanistically, 6ME inhibited fatty acid oxidation (FAO) by binding to and decreasing the activity of PPARδ, a transcription factor involved in FAO.

Methods: AML cell lines and patient-derived cells were used to assess the activity of 6ME in vitro and in vivo. Computational methods, immunoblotting, and co-IP-HPLC analysis assessed the molecular target, and cellular consequence of 6ME activity.

Results: 6ME induced cytotoxicity of AML cell lines (IC₅₀: 1.0 ± 0.13 μM) and patient-derived cells while sparing normal hematopoietic cells. Mouse engraftment studies showed that 6ME (5 mg/kg, three times/week for 4 weeks) selectively reduced patient-derived AML cell engraftment without affecting hematopoietic cell engraftment or imparting toxicity. Mechanistically, 6ME bound to and inhibited PPARδ leading to downregulated FAO gene expression (i.e., CD36 and CPT2) and reduced fatty acid cellular uptake resulting in FAO inhibition.

Conclusion: Pharmacological inhibition of PPARδ with 6ME is a novel approach to inducing selective death in AML.

Lipid accumulation is associated with breast cancer metastasis. However, the mechanisms underlying how breast cancer cells increase lipid stores and their functional role in disease progression remain incompletely understood. Herein we quantified changes in lipid metabolism and characterized cytoplasmic lipid droplets in metastatic versus non-metastatic breast cancer cells. ¹⁴C-labeled palmitate was used to determine differences in fatty acid (FA) uptake and oxidation. Despite similar levels of palmitate uptake, metastatic cells increase lipid accumulation and oxidation of endogenous FAs compared to non-metastatic cells. Isotope tracing also demonstrated that metastatic cells support increased de novo lipogenesis by converting higher levels of glutamine and glucose into the FA precursor, citrate. Consistent with this, metastatic cells displayed increased levels of fatty acid synthase (FASN) and de novo lipogenesis. Genetic depletion or pharmacologic inhibition of FASN reduced cell migration, survival in anoikis assays, and in vivo metastasis. Finally, global proteomic analysis indicated that proteins involved in proteasome function, mitotic cell cycle, and intracellular protein transport were reduced following FASN inhibition of metastatic cells. Overall, these studies demonstrate that breast cancer metastases accumulate FAs by increasingde novo lipogenesis, storing TAG as cytoplasmic lipid droplets, and catabolizing these stores to drive several FAO-dependent steps in metastasis.

Background: Human cells can synthesize methionine from homocysteine and folate-coupled methyl groups via the B₁₂-dependent enzyme methionine synthase (MTR). Yet, it has been known for decades that cancer cells fail to grow when methionine is replaced by homocysteine, a phenomenon known as methionine dependence. The underlying mechanism remains unknown.

Methods: Cancer cell lines were cultured with homocysteine in place of methionine, and growth responses were measured. Revertant cells capable of growing in homocysteine were generated through long-term culture with high B₁₂ and analyzed using single-cell RNA-seq. Metabolite uptake/release was measured using isotope dilution and MTR activity was assessed using metabolic flux analysis (MFA). Functional rescue experiments were performed by overexpressing the B₁₂-independent methionine synthase enzyme.

Results: We report evidence that methionine dependence is caused by low MTR activity secondary to a B₁₂ deficiency. High levels of the B₁₂ cofactor were required to revert methionine-dependent cancer cells to grow on homocysteine. The adapted "revertant" cells display gene expression signatures consistent with reduced invasion and metastasis. Metabolic flux analysis indicated that methionine-dependent cells do not fully activate MTR when cultured in homocysteine. High concentrations of homocysteine partially rescued growth of methionine-dependent cells. Expression of a B₁₂-independent methionine synthase enzyme in cancer cells restored growth on homocysteine and normalized the SAM:SAH ratio, while overexpression of the B₁₂-dependent human enzyme had no effect.

Conclusion: Methionine dependence in cancer can be driven by low MTR activity secondary to B₁₂ deficiency, at least in the cell lines studied. This mechanistic insight resolves a long-standing question in cancer metabolism and may open new avenues for exploiting the phenomenon for cancer therapy.

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.