MYC is dysregulated in approximately 70% of human cancers, strongly suggesting its essential function in cancer. MYC regulates many biological processes, such as cell cycle, metabolism, cellular senescence, apoptosis, angiogenesis, and immune escape. MYC plays a central role in carcinogenesis and is a key regulator of tumor development and drug resistance. Therefore, MYC is one of the most alluring therapeutic targets for developing cancer drugs. Although the search for direct inhibitors of MYC is challenging, MYC cannot simply be assumed to be undruggable. Targeting the MYC-MAX complex has been an effective method for directly targeting MYC. Alternatively, indirect targeting of MYC represents a more pragmatic therapeutic approach, mainly including inhibition of the transcriptional or translational processes of MYC, destabilization of the MYC protein, and blocking genes that are synthetically lethal with MYC overexpression. In this review, we delineate the multifaceted roles of MYC in cancer progression, highlighting a spectrum of therapeutic strategies and inhibitors for cancer therapy that target MYC, either directly or indirectly.

Oxaliplatin resistance poses a significant challenge in colorectal cancer (CRC) treatment. Recent studies have implicated CPSF6 in cancer progression and drug resistance, although its role in chemotherapy resistance and regulatory mechanisms is unclear. This study investigates CPSF6's involvement in oxaliplatin resistance in CRC and its regulation via m6A methylation by METTL3. We assessed CPSF6 expression in oxaliplatin-resistant (OxR) CRC cell lines (HT29-OxR and HCT116-OxR) compared to sensitive counterparts using qRT-PCR and Western blotting. CPSF6 was significantly upregulated in OxR cells, and its knockdown reduced cell viability, colony formation, and glycolytic activity while increasing apoptosis. m6A modification of CPSF6 mRNA was elevated in OxR cells, correlating with increased METTL3 expression. METTL3 knockdown decreased CPSF6 levels and m6A enrichment, enhancing mRNA degradation, while its overexpression stabilized CPSF6 mRNA, promoting resistance. Xenograft experiments showed that CPSF6 knockdown suppressed tumor growth and glycolysis. Thus, CPSF6 is identified as a mediator of oxaliplatin resistance in CRC, regulated by the METTL3/m6A axis, suggesting potential therapeutic targets to overcome resistance.

Metabolic reprogramming, a hallmark of malignancy, enables tumor cells to adapt to the harsh and dynamic tumor microenvironment (TME) by altering metabolic pathways. Hypoxia, prevalent in solid tumors, activates hypoxia inducible factor 1α (HIF-1α). HIF-1α drives metabolic reprogramming, enhancing glycolysis primarily through the Warburg effect to reduce oxygen dependence and facilitate tumor cell growth/proliferation. The above process is associated with accelerated tumor cell dedifferentiation and enhanced stemness, generating cancer stem cells (CSCs) which possesses the potential for self-renewal and differentiation that can differentiate into a wide range of subtypes of tumor cells and fuel tumor heterogeneity, metastasis, and recurrence, complicating therapy. This review examines the HIF-1α-glycolysis-dedifferentiation crosstalk mechanisms, expecting that indirect inhibition of HIF-1α by targeting metabolic enzymes, metabolites, or their signaling pathways will offer an effective therapeutic strategy to improve the cancer treatment outcomes.

Approximately 10-20% of patients with pheochromocytoma or sympathetic paraganglioma (PPGL) develop metastatic disease, most often as metachronous lesions. Unfortunately, there is a lack of accurate biomarkers that can predict the biologic behavior of a PPGL at the initial diagnosis. We investigated tumor samples from patients with PPGL and a diagnosis of either localized or metastatic disease with synchronous or metachronous metastases and performed a comprehensive molecular analysis through application of single-cell whole-genome sequencing and bulk transcriptome analysis, including variant detection analysis of RNA sequences. We found that PPGL displayed complex karyotypes with recurrent aneuploidies and substantial cell-to-cell karyotype variability, indicating ongoing chromosomal instability (CIN) in both localized and metastatic tumors. Transcriptome analysis on the other hand revealed several differences between localized and metastatic PPGL including TNFα and TGFβ signaling in metastatic PPGL that were already detectable in primary tumor samples of initially non-metastatic-appearing PPGLs that developed metachronous metastases. Altogether our findings indicate that while localized and metastatic PPGL in general have comparable genomic landscapes, they do show transcriptional differences that are already detectable in primary tumor PPGL before development of metastases. This finding could provide an important tool for improvement of patient stratification at initial diagnosis.

Metabolic reprogramming of tumor cells dynamically reshapes the distribution of nutrients and signals in the tumor microenvironment (TME), affecting intercellular interactions and resulting in metabolic immune suppression. Increased glucose uptake and metabolism are characteristic of many tumors. Meanwhile, the progression of colorectal carcinoma (CRC) relies on lipid metabolism. Therefore, investigating the role of glucolipid metabolic reprogramming on tumor immunity contributes to identifying new targets for immune suppression intervention in CRC. Our previous work demonstrated that SIRT1 is the hub gene involved in glucolipid metabolic conversion in CRC. Here, it is found that upregulated SIRT1 in CRC cells increases Treg functionality by promoting the secretion of CX3CL1. The CX3CL1-CX3CR1 signaling activated transcription factors SATB1 and BTG2, promoting the differentiation of TCF7+ Treg cells into functionally enhanced TNFRSF9+ Treg cells. Multiplex immunofluorescence (mIHC) analysis of a CRC tissue microarray confirmed the promoting effect of CX3CL1 on Treg infiltration. Additionally, the therapeutic efficacy of CX3CR1 inhibitor monotherapy and combination therapy is validated with the PD-1 antibody in the humanized subcutaneous CRC mouse model. This study elucidates a potential mechanism that metabolic reprogramming of cancer cells collaborates with subsequent immunosuppression to promote CRC progression.

At different stages of life, from embryonic to postnatal, varying oxygen concentrations modulate cellular gene expression by enhancing or repressing hypoxia-inducible transcription factors. During embryonic/fetal life, these genes encode proteins involved in adapting to a low-oxygen environment, including the induction of specific enzymes related to glycolytic metabolism, erythropoiesis, angiogenesis, and vasculogenesis. However, oxygen concentrations fluctuate during intrauterine life, enabling the induction of tissue-specific differentiation processes. Fetal well-being is thus closely linked to the physiological benefits of a dynamically hypoxic environment. Premature birth entails the precocious exposure of the immature fetus to a more oxygen-rich environment compared to the womb. As a result, preterm newborns face a condition of relative hyperoxia, which alters the postnatal development of organs and contributes to prematurity-related diseases. However, until recently, the molecular mechanism by which high oxygen tension alters normal fetal differentiation remained unclear. In this review, we discuss the research trajectory followed by our research group, which suggests that early exposure to a relatively hyperoxic environment may impair preterm neonates due to reduced expression of the β3-adrenoceptor. Additionally, we explore how these impairments could be prevented through the pharmacological stimulation of the remaining β3-adrenoceptors. Recent preclinical studies demonstrate that pharmacological stimulation of the β3-adrenoceptor can decouple exposure to hyperoxia from its harmful effects, offering a glimpse of the possibility to recreating the conditions typical of intrauterine life, even after premature birth.

Saccharomyces cerevisiae predominantly ferments sugar to ethanol, irrespective of the presence of oxygen, which is known as the Crabtree-effect. Traditional methods rely on static controls of glycolytic flux to make S. cerevisiae Crabtree-negative, which are not favorable for future biomanufacturing applications. Considering native metabolic pathways typically harness dynamic regulatory networks, we therefore aim to develop an alternative strategy using dynamic regulation of the yeast central metabolism to generate Crabtree-negative S. cerevisiae. We report that manipulating a single step at sugar phosphorylation can alter the mode of yeast metabolism with an attenuated Crabtree-effect. By implementing catabolite-regulated sugar phosphorylation, the diauxic shift in budding yeast was effectively reduced. The Crabtree-attenuated metabolism in the engineered yeast was confirmed by multidimensional characterizations such as cell morphology, the measurements of sugar utilization rate and ethanol production, and transcriptomics. In addition, we demonstrated that the Crabtree-attenuated metabolism could substantially improve the mitochondrial synthesis of short branched-chain fatty acids from amino acid catabolism, and allow the synthesis and accumulation of retinaldehyde. Taken together, we present for the first time that manipulation of sugar phosphorylation can alter the mode of yeast metabolism, and the synthetic Crabtree-attenuated yeast factory established here might serve as a non-fermentative biomanufacturing chassis.

Tumor acidosis causes resistance to immune checkpoint blockade (ICB). We hypothesized that a "pH-sensitizer" can increase tumor extracellular pH (pHe) and improve tumor control following ICB. We also hypothesized that pHe measured with acidoCEST MRI can predict improved tumor control with ICB.

We tested the effects of pH-sensitizers on proton efflux rate (PER), cytotoxicity, T cell activation, tumor immunogenicity, tumor growth and survival using 4T1 and B16-F10 tumor cells. We measured in vivo tumor pHe of 4T1 and B16-F10 models with acidoCEST MRI.

Among the pH-sensitizers tested, someprazole caused the greatest reduction in PER without exhibiting cytotoxicity or reducing T cell activation. Esomeprazole improved 4T1 tumor control with ICB administered one day after the pH-sensitizer. Tumor pHe positively correlated with TCF-1 + CD4 effector and CD8 T cell intratumoral frequencies and predicted improved 4T1 tumor control with ICB. For comparison, esomeprazole had a mild effect on B16-F10 tumor pHe, and worsened tumor control with ICB and increased intratumoral myeloid and dendritic cell (DC) frequencies.

A pH-sensitizer can improve tumor control with ICB, and acidoCEST MRI can be used to measure pHe and predict tumor control, but only in the 4T1 model and not the B16-F10 model.

Bladder cancer (BCa) is an aggressive malignancy of urinary system. Aerobic glycolysis refers to the phenomenon wherein cancer cells increase glucose consumption and produce lactic acid. Our study focused on the role and mechanism of circST6GALNAC6 in BCa glycolysis. The 24 h glucose intake was detected using flow cytometry. Lactic acid and ATP were detected in BCa cells utilizing commercially provided kits. Extracellular acidification rate was measured using Seahorse XF-96p Extracellular Flux Analyzer. Cell proliferation was determined using colony formation assay. RNA immunoprecipitation and co-immunoprecipitation experiments were adopted to validate molecular interactions. BALB/C nude mice were utilized to establish xenograft tumor model. CircST6GALNAC6 was decreased in BCa cells, and overexpression of circST6GALNAC6 inhibited glycolysis and proliferation of BCa cells. Additionally, overexpression of circST6GALNAC6 promoted the degradation of glycolytic regulatory protein HK1 and decreased its expression, and PRKN facilitated ubiquitination-related degradation of HK1. CircST6GALNAC6 enhanced the mRNA stability and expression of PRKN by recruiting FUS. Furthermore, the inhibitory impact of circST6GALNAC6 overexpression on glycolysis in BCa cells was reversed by PRKN knockdown. Finally, overexpression of circST6GALNAC6 suppressed tumor growth through increasing PRKN in nude mice. CircST6GALNAC6 suppressed glycolysis in BCa through FUS/PRKN/HK1 axis. Targeting circST6GALNAC6 holds promise as a novel approach for treating BCa.

In Parkinson's disease (PD), the disturbance of energy metabolism due to glucose metabolic reprogramming may be a critical factor contributing to neuronal degeneration and death. Glycolysis, as the core process of glucose metabolism, not only serves as a fundamental source of energy but also integrates various metabolic pathways. However, the precise role of alterations in glycolysis-related pathways in the progression of PD remains elusive. We compared and analysed datasets from human databases of patients with PD and healthy controls to identify differentially expressed genes associated with glycolysis. Using the least absolute shrinkage and selection operator regression method and multivariate logistic regression analysis, we identified glucan-branching enzyme 1 (GBE1) as the most confident glycolytic gene implicated in PD. We validated the low expression of GBE1 in 1 - methyl - 4 - phenyl - 1,2,3,6 - tetrahydropyridine (MPTP)-induced PD animal models. Stereotaxic injection-mediated overexpression of GBE1 in striatal neurons improved motor dysfunction in these animal models. In vitro experiments demonstrated that GBE1 promotes the expression of lactate dehydrogenase A (LDHA) and lactate dehydrogenase B (LDHB), enhances cellular glycolytic flux, and thereby increases the viability of PC12 cells under MPP+ treatment. Additionally, GBE1 alleviates mitochondrial dysfunction and restores oxidative phosphorylation in PD. In summary, by integrating machine learning and bioinformatics approaches, we identified GBE1, a glycolysis-related gene with significant implications for PD, elucidating its crucial role in glucose metabolic reprogramming and identifying potential therapeutic targets for modulating glucose metabolism in PD.

By correcting the effect of tumor size on metabolic activity, the maximum standardized uptake value-to-tumor size (SUVmax:tumor size) ratio on fluorodeoxyglucose F18 positron emission tomography (18F-FDG PET)/computed tomography (CT) scans can be a prognostic parameter of non-small cell lung cancer (NSCLC). The current study evaluates the prognostic value of SUVmax:tumor size ratio on pretreatment 18F-FDG PET/CT scans in patients with NSCLC. Furthermore, the SUVmax:tumor size ratio is compared with other established PET parameters.

This study included 108 patients with NSCLC who underwent pretreatment 18F-FDG PET/CT scans and curative lung surgery. The associations between the SUVmax:tumor size ratio and other conventional PET parameters were investigated. The recurrence-free survival according to the SUVmax:tumor size ratio was also analyzed. In addition, the SUVmax:tumor size ratio was compared according to postoperative pathologic findings.

In total, 72 (66.7%) of the 108 participants presented with adenocarcinoma (ADC). Nineteen (17.6%) patients experienced recurrence during a median follow-up period of 32.3 months. The median SUV max:tumor size ratio was 2.37 (1.23 for ADCs and 3.90 for other histologic types). The SUVmax:tumor size ratio was associated with SUVmax and mean SUV, as well as metabolic tumor volume and total lesion glycolysis. Patients with an SUVmax:tumor size ratio higher than the median had a worse recurrence outcome than those with an SUVmax:tumor size ratio lower than the median. Participants with ADC who presented with lymphovascular invasion had a higher SUVmax:tumor size ratio than those without. The presence of lymph node metastasis and advanced histologic grade were associated with a high SUVmax:tumor size ratio in patients with ADC.

The SUVmax:tumor size ratio on pretreatment 18F-FDG PET/CT scans was associated with aggressive tumor behavior and poor outcome in NSCLCs, particularly ADC.

The SUVmax:tumor size ratio on pretreatment 18F-FDG PET/CT scans has a prognostic value in patients with NSCLCs, especially ADC.

Sebaceous glands synthesize and secrete sebum, a mélange of lipids and other cellular products that safeguards the mammalian integument. Differentiating sebocytes delaminate from the basal membrane and dislodge towards the gland's middle, where they eventually undergo a poorly understood death mode in which the whole cell becomes a secretion product (holocrine secretion). Supported by recent transcriptomics data, this review examines the idea that peripheral sebocytes have a remarkable ability to draw nutrients from the blood and become committed to unrestrainedly invest all available resources into synthetic processes for accomplishing sebum synthesis, thereby exploiting core metabolic fluxes as glycogen turnover, glutamine-directed anaplerosis, the pentose phosphate pathway and de novo lipogenesis. Finally, we propose that metabolic-driven processes are an important mechanistic component of holocrine secretion. A deeper understanding of these metabolic adaptations could indicate novel strategies for modulating sebum synthesis, a key pathogenic factor in acne and other skin diseases.

Small cell lung cancer (SCLC) is one of the malignancies with the worst prognosis, and there have been no major breakthroughs in its treatment for a long time. The majority of patients are diagnosed at the extensive stage, where the only option is chemotherapy, and even the addition of immune checkpoint inhibitors results in only modest benefits. The characterization of the molecular mechanisms behind therapy resistance has relevance in finding novel therapeutic approaches. Previous studies showed the possibility of annexin A1's (ANXA1) involvement in the immunosuppressive tumor microenvironment in SCLC, and there are studies showing the direct effects of ANXA1 modulation on cancer cell aggressiveness.

We aimed to characterize the roles of ANXA1 expression using publicly available transcriptomic data, the RNA-seq-based predictive algorithms EPIC and ESTIMATE, and immunohistochemistry on patient samples. For the in vitro studies, we silenced ANXA1 expression with short hairpin RNA in three SCLC cell lines, measured the growth rate with the trypan blue exclusion assay, assessed the chemosensitivity to cisplatin and etoposide with the Presto BlueTM viability assay, and performed Western blots to assess changes in the levels of metabolic and mesenchymal markers and transcriptional drivers.

ANXA1-high tumors are associated with significantly increased immune infiltrates, stromality, and tumor-associated macrophages (TAMs). The ANXA1 protein is expressed on tumor cells and TAMs at the tissue level. ANXA1 silencing in H841 cells did not affect the growth rate; in SW1271 cells, shANXA1 cells grew significantly slower than shCTRL cells. Meanwhile, in H1048 cells, proliferation was significantly faster. Despite the different growth rates of the tested cell lines, ANXA1 silencing decreased the chemosensitivity to both cisplatin and etoposide in all three cell lines. Gene expression changes in mesenchymal markers, metabolic markers, dominant transcriptional drivers, and immune-relevant molecules were also characterized.

This is the first comprehensive characterization of ANXA1 in SCLC to reveal its role in the tumor's cell biology and the TME, aiming to boost further research in the field.

Crabtree-positive yeasts rapidly consume glucose via glycolysis, making it difficult to experimentally estimate their actual glycolytic rate or flux. We present a stable isotope labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based protocol to quantitatively estimate glycolytic and related carbon metabolic fluxes using Saccharomyces cerevisiae. This approach defines time windows to capture glucose metabolic intermediate production before label saturation, enabling a comparison of glycolytic flux changes across different cells. This protocol provides a reliable, quantitative approach to study dynamic metabolic fluxes in these cells. For complete details on the use and execution of this protocol, please refer to Vengayil et al., 2024.1.

Metabolic reprogramming, a well-established hallmark of gastric carcinogenesis, has been implicated in driving tumor progression. Nevertheless, the precise mechanisms through which these metabolic alterations orchestrate gastric cancer (GC) pathogenesis remain incompletely elucidated. We conducted metabolomic analyses of plasma samples obtained from 334 patients with GC and healthy individuals to identify differential metabolites and metabolic pathways. Transcriptome sequencing was conducted on six pairs of tissues, and a joint analysis of the transcriptome and metabolome was performed. Single-cell sequencing data were acquired and co-analyzed with metabolomics to investigate metabolic abnormalities at the single-cell level. Finally, four representative metabolites selected using Random Forest analysis were subjected to cellular experiments to elucidate the mechanisms through which these metabolites exert their effects. Metabolomic analyses revealed that serine and glycine metabolism, glycolysis, and glutamate metabolism were significantly altered in GC, suggesting that one-carbon metabolism (1CM)-related pathways are aberrantly activated. A combined analysis of the transcriptome, single-cell transcriptome, and metabolomics indicated that pathways related to oxidative phosphorylation, nucleotide metabolism, and amino acid metabolism in epithelial cells were altered in GC. Cellular experiments demonstrated that the one-carbon donor metabolite betaine could inhibit the activity, invasion, and migration of GC cells while activating the phosphorylation of AMPKα. In conclusion, the 1CM-related pathway and the metabolite betaine play significant roles in GC, and the mechanisms through which the one-carbon donor betaine influences GC warrant further investigation.

Traffic-related ultrafine particles (UFPs) are an emerging health concern affecting the brain and increasing the risk of Alzheimer's disease (AD). PI3K/AKT signaling is known to contribute to neuronal survival and to be altered in AD. The nasal olfactory mucosa (OM) is a sensory tissue exposed directly to ambient air, and a starting point for olfactory neural circuits towards the brain. Evidence of air pollution-induced transcriptional regulation via microRNAs (miRNA) and DNA methylation (DNAmet) is accumulating and air pollutant-mediated disturbances in PI3K/AKT signaling have been reported. By utilizing a highly translational human-based in vitro model of OM, we aimed to investigate possible gene regulatory mechanisms in PI3K/AKT signaling induced by UFPs, and to compare the responses between cognitively healthy and individuals with AD. miRNA expression was analyzed using next-generation sequencing (NGS) and chip-based methylation analysis was performed to detect differentially methylated loci (DML). These data were combined with previously published transcriptomics analysis (mRNA) to construct an mRNA-miRNA-DNAmet-integrative network. Protein level changes were studied by immunoassays. We observed UFP-induced reductions in viability and increases in oxidative stress and DNA damage without eminent cell death. Integrative network analysis revealed multiple connections of miRNAs to differentially expressed genes in the PI3K/AKT pathway, and effects were most prominent in AD cells. Similarly, in AD cells DML were identified in transcription factor and apoptosis genes, downstream of PI3K/AKT signaling. Conclusively, traffic-related UFPs influence gene regulation of PI3K/AKT signaling to modulate OM cell survival, with existing AD pathology resulting in heightened vulnerability to UFP effects.

Background/Objectives: Cancer cells often display altered energy metabolism. In particular, expression levels and activity of the tricarboxylic acid cycle (TCA cycle) enzymes may change in cancer, and dysregulation of the TCA cycle is a frequent hallmark of cancer cell metabolism. MEMO1, a modulator of cancer metastasis, has been shown to bind iron and regulate iron homeostasis in the cells. MEMO1 knockout changed mitochondrial morphology and iron content in breast cancer cells. Our previous genome-wide analysis of MEMO1 genetic interactions across multiple cancer cell lines revealed that gene sets involved in mitochondrial respiration and the TCA cycle are enriched among the gain-of-function interaction partners of MEMO1. Based on these findings, we measured the TCA cycle metabolite levels in breast cancer cells with varying levels of MEMO1 expression. Methods: ShRNA knockdown assay was performed to test essentiality of key TCA cycle enzymes. TCA metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in MDA-MB-231 (high MEMO1), M67-2 (MEMO1 knockdown), and M67-9 (MEMO1 knockout) cells under iron-depleted, basal iron, and iron-supplemented conditions. Results:ACO2 and OGDH knockdowns inhibit cell proliferation, indicating an essential role of the TCA cycle in MDA-MB-231 metabolism. α-Ketoglutarate and citrate levels exhibited an inverse relationship with MEMO1 expression, increasing significantly in MEMO1 knockout cells regardless of iron availability. In contrast, fumarate, malate, and glutamate levels were elevated in MEMO1 knockout cells specifically under low iron conditions, suggesting an iron-dependent effect. Conclusions: Overall, our results indicate that MEMO1 plays a role in regulating the TCA in cancer cells in an iron-dependent manner.

Exploring the anti-tumor molecular mechanisms of traditional Chinese medicines has become an important strategy to develop novel anti-tumor drugs in the clinic. Several pharmacological studies have reported the antioxidant, antibacterial, anti-inflammatory, and anti-tumor effects of clove. Previously, we have shown that the active fraction from clove (AFC) can inhibit the growth of tumor cells, particularly colon cancer cells, in vitro. However, the mechanism of action regarding the anti-colon cancer activity of AFC, especially in aerobic glycolysis, has not been adequately investigated. In this study, we found that AFC significantly inhibited the growth of five types of colon cancer cells, downregulated the mRNA and protein levels of M2-type pyruvate kinase (PKM2), and reduced aerobic glycolysis capacity. Transfection of PKM2-siRNA mimicked the inhibitory effects of AFC on aerobic glycolysis in colon cancer cells. Furthermore, the highly expressed, tumor-specific targets c-myc and cyclin D1 in cells were also found to be downregulated following the action of AFC. In the HCT116 cell xenograft nude mice models, the results after AFC administration were consistent with those of the cellular experiments, while AFC caused less liver injury and weight loss than the conventional chemotherapeutic agent 5- fluorouracil (5-FU). In conclusion, AFC inhibits colon cancer growth by downregulating PKM2 to inhibit aerobic glycolysis and reduce the tumor-specific high expression of c-myc and cyclin D1. Future work should explore how it downregulates pyruvate kinase (PK) in the first place, along with the intrinsic mechanism between the downregulation of PKM2 and the downregulation of c-myc.

Photothermal therapy has been observed to upregulate the heat shock protein 70 (HSP 70) expression in tumor cells, consequently diminishing the anti-tumor efficacy of the treatment. The expression of HSP 70 is intricately linked to the adenosine triphosphate (ATP) levels within tumors, suggesting that modulating energy metabolism could potentially enhance the effectiveness of photothermal therapy. To address these challenges, ATO-QUE-Fe2+-PVP K30 nanoparticles (AQFP NPs) were synthesized through the coordinated self-assembly of the oxidative phosphorylation (OXPHOS) inhibitor atovaquone (ATO) and the glycolysis inhibitor quercetin (QUE) with ferrous ions (Fe2+) for synergetic energy depletion and low-temperature photothermal therapy (LTPTT). The synthesized AQFP NPs exhibited a small particle size and demonstrated high encapsulation efficiency of ATO and QUE. AQFP NPs could effectively downregulate the expression of HSP 70 by inhibiting the activity of mitochondrial complex Ⅲ and hexokinase Ⅱ (HK Ⅱ) to inhibiting suppress mitochondrial OXPHOS and glycolytic pathways in 4T1 cells, respectively. This inhibition resulted in a reduction of ATP levels within tumor cells, subsequently leading to decreased expression of HSP 70 and enhancing the therapeutic efficacy of LTPTT. Furthermore, AQFP NPs can remarkably inhibit the growth of tumors when subjected to laser irradiation. Furthermore, the analysis of blood biochemical indices and hematoxylin and eosin (H&E) staining of major organs suggested that AQFP NPs exhibit a preferable in vivo safety profile. In conclusion, the anti-tumor efficacy of LTPTT could be substantially enhanced by concurrently inhibiting OXPHOS and glycolysis, thereby offering an innovative therapeutic for the clinical treatment of tumors.

Cell cycle progression is timely interconnected with oscillations in cellular metabolism. Here, we first describe how these metabolic oscillations allow cycling cells to meet the bioenergetic needs specifically for each phase of the cell cycle. In parallel, we highlight how the cytosolic level of citrate is dynamically regulated during these different phases, being low in G1 phase, increasing in S phase, peaking in G2/M, and decreasing in mitosis. Of note, in cancer cells, a dysregulation of such citrate oscillation can support cell cycle progression by promoting a deregulated Warburg effect (aerobic glycolysis), activating oncogenic signaling pathways (such as PI3K/AKT), and promoting acetyl-CoA production via alternative routes, such as overconsumption of acetate. Then, we review how administration of sodium citrate (at high doses) arrests the cell cycle in G0/G1 or G2/M, inhibits glycolysis and PI3K/AKT, induces apoptosis, and significantly reduces tumor growth in various in vivo models. Last, we reason on the possibility to implement citrate administration to reinforce the effectiveness of cell cycle inhibitors to better cure cancer.

Otto Warburg originally proposed that cancer arose from a two-step process. The first step involved a chronic insufficiency of mitochondrial oxidative phosphorylation (OxPhos), while the second step involved a protracted compensatory energy synthesis through lactic acid fermentation. His extensive findings showed that oxygen consumption was lower while lactate production was higher in cancerous tissues than in non-cancerous tissues. Warburg considered both oxygen consumption and extracellular lactate as accurate markers for ATP production through OxPhos and glycolysis, respectively. Warburg's hypothesis was challenged from findings showing that oxygen consumption remained high in some cancer cells despite the elevated production of lactate suggesting that OxPhos was largely unimpaired. New information indicates that neither oxygen consumption nor lactate production are accurate surrogates for quantification of ATP production in cancer cells. Warburg also did not know that a significant amount of ATP could come from glutamine-driven mitochondrial substrate level phosphorylation in the glutaminolysis pathway with succinate produced as end product, thus confounding the linkage of oxygen consumption to the origin of ATP production within mitochondria. Moreover, new information shows that cytoplasmic lipid droplets and elevated aerobic lactic acid fermentation are both biomarkers for OxPhos insufficiency. Warburg's original hypothesis can now be linked to a more complete understanding of how OxPhos insufficiency underlies dysregulated cancer cell growth. These findings can also address several questionable assumptions regarding the origin of cancer thus allowing the field to advance with more effective therapeutic strategies for a less toxic metabolic management and prevention of cancer.

The extent of mitochondrial heterogeneity and the presence of mitochondrial archetypes in cancer remain unknown. Mitochondria play a central role in the metabolic reprogramming that occurs in cancer cells. This process adjusts the activity of metabolic pathways to support growth, proliferation, and survival of cancer cells. Using a panel of colorectal cancer (CRC) cell lines, we revealed extensive differences in their mitochondrial composition, suggesting functional specialisation of these organelles. We differentiated bioenergetic and mitochondrial phenotypes, which point to different strategies used by CRC cells to maintain their sustainability. Moreover, the efficacy of various treatments targeting metabolic pathways was dependent on the respiration and glycolysis levels of cancer cells. Furthermore, we identified metabolites associated with both bioenergetic profiles and cell responses to treatments. The levels of these molecules can be used to predict the therapeutic efficacy of anti-cancer drugs and identify metabolic vulnerabilities of CRC. Our study indicates that the efficacy of CRC therapies is closely linked to mitochondrial status and cellular bioenergetics.

Increasing lines of evidence link the expression of the interferon-stimulated gene RSAD2, encoding the antiviral enzyme, viperin, to autoimmune disease. Autoimmune diseases are characterized by chronic overproduction of cytokines such as interferons that upregulate the inflammatory response. Immune cells exposed to interferon selectively downregulate transcription of the mitochondrially encoded components of the oxidative phosphorylation system, which leads to mitochondria becoming dysfunctional and impairing their ability to produce ATP. But the mechanism by which downregulation occurs has remained unknown. Here we show that 3'-deoxy-3',4'-didehydrocytidine triphosphate (ddhCTP) which is synthesized by viperin suppresses mitochondrial transcription by causing premature chain termination when misincorporated by the mitochondrial RNA polymerase (POLRMT). We show that viperin expression in human cell lines downregulates mitochondrially encoded gene expression. A similar effect is observed across multiple cell lines when cells are exposed to ddhC, the precursor to ddhCTP. The pattern of gene downregulation fits well with a simple, quantitative model describing chain-termination. In vitro measurements with purified POLRMT demonstrate that ddhCTP competes effectively with CTP, leading to its misincorporation into RNA. These findings reveal a new molecular mechanism for mitochondrial transcriptional regulation that explains the reduction in mitochondrially-encoded transcript levels in response to chronic interferon stimulation, characteristic of inflammatory diseases.

Cancer is characterized by accelerated glycolysis with enhanced glucose uptake and lactate production, a phenomenon termed Warburg effect (WE). We studied the incidence and clinical impact of Warburg-driven lactic acidosis in lymphoma.

Patients admitted with newly diagnosed or relapsed/refractory lymphoma and documented lactate levels during the first week of admission were included. Patients with lactatemia were classified as secondary (with a recognizable cause for elevated lactate) or none (WE group).

WE and secondary lactatemia were documented in 58 and 44 patients (15% and 12% of evaluable patients, respectively). Both WE and secondary lactatemia were associated with poor short-term survival. WE at presentation correlated with tumor burden, with most patients having aggressive disease, advanced stage, and extranodal involvement. WE was associated with high rates of early death (26% and 43% at 30- and 60-days, respectively). Higher lactate levels correlated with worse survival. Earlier initiation of chemotherapy was associated with a (nonsignificant) trend toward better outcomes, whereas steroid and/or thiamine therapy did not alter patient outcomes. Glucose administration was associated with worse survival.

WE-driven lactatemia is associated with high tumor burden and increased short-term mortality in lymphoma. Prompt initiation of anti-lymphoma therapy may improve outcomes.

Cancer cells acquire metabolic advantages over their normal counterparts regarding the use of nutrients for sustained cell proliferation and cell survival in the tumor microenvironment. Notable among the metabolic traits in cancer cells is the Warburg effect, which is a reprogrammed form of glycolysis that favors the rapid generation of ATP from glucose and the production of biological macromolecules by diverting glucose into various metabolic intermediates. Meanwhile, mannose, which is the C-2 epimer of glucose, has the ability to dampen the Warburg effect, resulting in slow-cycling cancer cells that are highly susceptible to chemotherapy. This anticancer effect of mannose appears when its catabolism is compromised in cancer cells. Moreover, de novo synthesis of mannose within cancer cells has also been identified as a potential target for enhancing chemosensitivity through targeting glycosylation pathways. The underlying mechanisms by which alterations in mannose metabolism induce cancer cell vulnerability are just beginning to emerge. This review summarizes the current state of our knowledge of mannose metabolism and provides insights into its manipulation as a potential anticancer strategy.

Immunogenic cell death, triggered by photothermal therapy or specific chemotherapy, strives to establish a positive feedback loop in cancer immunotherapy. This loop is characterized by the rapid release of antigens and adenosine triphosphate (ATP), ultimately leading to accelerated T cell infiltration. However, this loop is hindered by T cell exhaustion caused by adenosine originating from ATP and glucose deprivation in the immunosuppressive microenvironment. To overcome this challenge, we developed a pH-low insertion peptide-functionalized mesoporous-polydopamine-based nanoadjuvant that incorporates adenosine deaminase and doxorubicin (termed as PPMAD). PPMAD aimed to overcome T cell exhaustion by reducing adenosine consumption and providing an alternative carbon source for CD8+ T cell function during glucose starvation. First, PPMAD triggered the burst release of antigens and ATP through photothermal therapy and doxorubicin-induced immunogenic cell death, culminating in the expedited infiltration of T cells. Second, adenosine deaminase depleted adenosine, reducing immunosuppressive agents and generating abundant inosine, which served as an alternative carbon source for CD8+ T cells. By implementing this "reducing suppression and broadening sources" strategy, we successfully overcome T cell exhaustion, greatly enhancing the effectiveness of cancer immunotherapy both in vitro and in vivo. Our findings highlighted the positive feedback loop between on-demand photothermal therapy, chemotherapy immunotherapy, and achieving complete tumor response.

Hypoxia-inducible factors (HIFs) are key regulators of intracellular oxygen homeostasis. The marked increase in HIFs activity in hypoxia as compared to normoxia, together with their transcriptional control of primary metabolic pathways, motivated the widespread view of HIFs as responsible for the cell's metabolic adaptation to hypoxic stress. In this work, we suggest that this prevailing model of HIFs regulation is misleading. We propose an alternative model focused on understanding the dynamics of HIFs' activity within its physiological context. Our model suggests that HIFs would not respond to but rather prevent the onset of hypoxic stress by regulating the traffic of electrons between catabolic substrates and oxygen. The explanatory power of our approach is patent in its interpretation of the Warburg effect, the tendency of tumor cells to favor anaerobic metabolism over respiration, even in fully aerobic conditions. This puzzling behavior is currently considered as an anomalous metabolic deviation. Our model predicts the Warburg effect as the expected homeostatic response of tumor cells to the abnormal increase in metabolic demand that characterizes malignant phenotypes. This alternative perspective prompts a redefinition of HIFs' function and underscores the need to explicitly consider the cell's metabolic activity in understanding its responses to changes in oxygen availability.

Mitochondrial-encoded circular RNAs (mecciRNAs) are a newly discovered class of mitochondrial-encoded non-coding RNAs (mt-ncRNAs) that play important biological roles in the cell. This study aimed to examine the expression profile of SCAR/mc-COX2 (has_circ_0089762) in colorectal cancer (CRC) and its relationship with clinicopathological variables. Furthermore, to better understand SCAR/mc-COX2's functional role in CRC, we constructed a competing endogenous RNA (ceRNA) network.

Quantitative real-time PCR (qRT-PCR) was employed to analyze the expression levels of SCAR/mc-COX2 in 40 pairs of CRC samples, consisting of 40 tumor samples and 40 adjacent non-tumoral samples from patients. The ceRNA regulatory network was constructed using online bioinformatics tools. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) enrichment analysis were conducted using the Enrichr database.

The results demonstrated a significant decrease in SCAR/mc-COX2 expression in tumor tissues compared to adjacent non-tumoral tissues (p-value<0.05). In another finding, a significant relationship was observed between pathological T staging and the expression status of SCAR/mc-COX2 (p-value=0.02). Additionally, the Receiver Operating Characteristic (ROC) curve analysis revealed that SCAR/mc-COX2 had an area under the curve (AUC) of 0.77, with 80% sensitivity and 75% specificity. Finally, a ceRNA regulatory network including SCAR/mc-COX2, 5 miRNA, and 9 mRNAs was found.

These findings suggest that SCAR/mc-COX2 may act as a tumor suppressor in CRC, and its dysregulation could play a crucial role in the pathophysiology of this cancer. The significant association with pathological T staging and its robust diagnostic performance (AUC = 0.77, sensitivity = 80%, specificity = 75%) highlight its potential as a novel biomarker for CRC detection and prognosis. Further functional studies are required to elucidate its precise role in CRC tumorigenesis and clinical applicability.

Ischemia-reperfusion injury (IRI) is a critical condition that poses a significant threat to patient safety. The production of lactate increases during the process of IRI, and lactate serves as a crucial indicator for assessing the severity of such injury. Lactylation, a newly discovered post-translational modification in 2019, is induced by lactic acid and predominantly occurs on lysine residues of histone or nonhistone proteins. Extensive studies have demonstrated the pivotal role of lactylation in the pathogenesis and progression of various diseases, including melanoma, myocardial infarction, hepatocellular carcinoma, Alzheimer's disease, and nonalcoholic fatty liver disease. Additionally, a marked correlation between lactylation and inflammation has been observed. This article provides a comprehensive review of the mechanism underlying lactylation in IRI to establish a theoretical foundation for better understanding the interplay between lactylation and IRI.

Histone lactylation, a newly glycosis-related histone modification, plays a crucial role in the regulation of gene expression in various immune cells. However, the role of histone lactylation in astrocytes remains unclear. Here, this study showed that the H3K18 lactylation (H3K18la) levels were upregulated in primary astrocytes under unconjugated bilirubin (UCB) stimulation and hippocampus of bilirubin encephalopathy (BE) rats. Inhibition of glycolysis decreased H3K18la and attenuated pyroptosis both in vitro and in vivo. CUT& Tag and RNA-seq results revealed that H3K18la was enriched at the promoter of nucleotide-binding oligomerization domain 2 (NOD2) and promoted its transcription. Moreover, NOD2 boosted the activation of downstream mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, which exacerbated the neuroinflammation of BE. Collectively, this study provides a novel understanding of epigenetic regulation in astrocytes, and interruption of the H3K18la/NOD2 axis may represent a novel therapeutic strategy for treating bilirubin encephalopathy.

Not all polysaccharides function as antitumor drugs, nor do they universally possess the same advantages regarding safety and biocompatibility. Those polysaccharides that are effective antitumor agents typically demonstrate superior safety profiles and biocompatibility compared to synthetic anticancer drugs, which can exhibit high toxicity and harmful side effects. Dendrobium huoshanense polysaccharide (DHP) has been recognized for its potential bioactive properties, particularly in anti-tumor treatment. This study investigates the effects of DHP on the proliferation and apoptosis of HCT116 colon cancer cells.

DHP was extracted according to previously published experimental methods. The inhibitory effects of DHP were evaluated using IEC6, Caco-2, and HCT116 cell lines, with changes in cell morphology observed via transmission electron microscopy. After establishing the conditions for DHP administration, flow cytometry was employed to assess its effects on apoptosis, reactive oxygen species (ROS), and mitochondrial membrane potential of HCT116 cells. Additionally, immunoprecipitation, quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and biomarker detection were utilized to investigate the mechanisms underlying DHP's inhibition of HCT116 cells and its impact on metabolic reprogramming.

In the present study, we observed that DHP treatment at 600 μg/ml for 24 h reduced HCT116 cell viability to 54.87%. In contrast, the inhibitory effect of DHP on the viability of IEC6 and Caco-2 cells was relatively mild. The specific mechanism involves DHP activating the mitochondrial apoptotic pathway leading to the downregulation of key metabolic intermediates and enzymes such as uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) and ST6Gal-I. By inhibiting ST6Gal-I activity, DHP activates the Fas/FasL signaling pathway. Additionally, DHP-induced ROS production effectively triggers apoptosis in HCT116 cells.

Our study demonstrates that DHP effectively inhibits the proliferation and induces apoptosis in HCT116 colon cancer cells through the activation of the Fas-FasL signaling pathway and metabolic reprogramming. The selective inhibitory effect of DHP on HCT116 cells, the activation of both death receptor and mitochondrial apoptotic pathways, and the modulation of metabolic reprogramming provide novel insights into the potential therapeutic strategies for colon cancer.

Anaplastic thyroid cancer (ATC) has a dismal prognosis, and the optimal treatment has not yet been confirmed. Euphorbia fischeriana Steud has been proven to exhibit pharmacological properties, including various antitumor effects, that can be used to treat numerous diseases and has been used to treat cancer. 17-Hydroxy-jolkinolide B (17-HJB) is one of the major diterpenoids produced from plants, but little research has investigated how it affects cancer.

MTT assays, glucose and lactate concentration detection, Annexin V-FITC detection via cytometry, and Western blotting were performed to research the mechanism of 17-HJB.

Cell viability was inhibited in a concentration-dependent manner after 17-HJB treatment. 17-HJB inhibited glucose consumption and lactate production, and the expression of the glucose transporter GLUT1 and proteins associated with glycolysis, HK2, PFK1, and PKM2, was significantly downregulated. 17-HJB induced apoptosis, and the expression of signaling proteins related to apoptosis, such as Caspase-3 and cleaved Caspase-3, was upregulated. In vivo, 17-HJB effectively inhibited the growth of ATC tumors. The results of the expression of glycolysis-related enzyme proteins and apoptosis signaling proteins were consistent with those in vitro.

17-HJB inhibited the growth of ATCs both in vivo and in vitro. The mechanism may be related to the effects on glucose metabolism and the inhibition of aerobic glycolysis. 17-HJB also induced ATC apoptosis.

The rising trend in global cancer incidence has caused widespread concern, one of the main reasons being the aging of the global population. Statistical data show that cancer incidence and mortality rates show a clear upward trend with age. Although there is a commonality between dysregulated nutrient sensing, which is one of the main features of aging, and metabolic reprogramming of tumor cells, the specific regulatory relationship is not clear. This manuscript intends to comprehensively analyze the relationship between senescence and tumor metabolic reprogramming; as well as reveal the impact of key factors leading to cellular senescence on tumorigenesis. In addition, this review summarizes the current intervention strategies targeting nutrient sensing pathways, as well as the clinical cases of treating tumors targeting the characteristics of senescence with the existing nanodelivery research strategies. Finally, it also suggests sensible dietary habits for those who wish to combat aging. In conclusion, this review attempts to sort out the link between aging and metabolism and provide new ideas for cancer treatment.

Prostate cancer (PCa) is the most prevalent cancer in men and the leading cause of cancer-related mortality. Recent studies have highlighted the pivotal role of glycolysis in tumor progression. This study aimed to investigate the involvement of the EDNRB gene and its ligand endothelin 3 (EDN3) in glycolysis in PCa and to elucidate its underlying molecular mechanism. Quantitative reverse transcription PCR (RT-qPCR) and methylation-specific PCR (MSP) were used to probe EDNRB expression and methylation in PCa tissues. Cell proliferation and glycolysis in PCa cells were evaluated using Cell Counting Kit-8 (CCK-8), EDU staining, Seahorse assay, and biochemical kits to analyze the effects of EDN3/EDNRB. The underlying molecular mechanism was further explored through Western blotting. The in vivo effect of EDNRB on tumor growth was examined using a xenograft tumor model. Our findings revealed that EDNRB was hypermethylated and downregulated in PCa tissues and cell lines. Overexpression of EDNRB or EDN3 led to reduced cell proliferation and downregulation of glycolytic markers. EDNRB also decreased the extracellular acidification rate (ECAR) baseline and increased the oxygen consumption rate (OCR) baseline, indicating a shift away from glycolysis. Additionally, the anticancer effects of EDNRB or EDN3 was reversed upon inhibition of the cGMP/PKG pathway. In vivo, enhanced EDNRB expression significantly suppressed tumor growth. Therefore, EDNRB or EDN3 possess anticancer potential in PCa, primarily through the regulation of glycolysis via the cGMP/PKG pathway.

Methylmalonic acid (MMA) is a small molecule produced during the metabolism of propionate and branched-chain amino acids. Recently, it has been reported that the blood concentration of MMA increases with age and promotes lung cancer metastasis. However, little is known regarding its effects on cancers other than lung cancer. In the present study, we examined the effects of MMA on colorectal cancer cell spheroids. We found that MMA promoted the proliferation of colorectal cancer spheroids at physiological concentrations that can be exhibited by the elderly and induced mitochondrial reactive oxygen species generation, which in turn affected the promotion of cell growth. MMA treatment also induces a metabolic shift in the glycolytic system. These results suggest that MMA may promote cancer cell proliferation by decreasing mitochondrial function, inducing a metabolic shift, and provide new insights into the effects of aging on cancer.

Lon protease 1 (LONP1) is an ATP-dependent protease located in the mitochondrial matrix and plays a crucial role in regulating mitochondrial proteostasis, metabolism, and cellular stress responses et al. Aberrant LONP1 expression has been found in the progression of various tumors; however, the role and molecular mechanisms of LONP1 in prostate cancer (PCa) remain poorly understood. Here we show that overexpression of LONP1 is closely related to adverse clinic pathological features and poor prognosis in PCa patients. Mechanistically, the findings reveal that LONP1 is implicated in modulating the metabolic switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, thereby promoting tumor proliferation, invasion, and metastasis both in vitro and in vivo. Meanwhile, we prove that LONP1 as a protease directly targets mitochondrial pyruvate carrier 1 (MPC1), a key metabolic protein in the process of glycolysis, and enhances its degradation, which in turn suppresses tricarboxylic acid (TCA) cycle and ultimately promotes the progression of PCa. Furthermore, using PCa in cancer-prone mice homozygous for a prostate-targeted conditional Pten knockout and Lonp1 knockin, we integrate transcriptomic and proteomic analyses of prostate tumors, upon which reveals that Lonp1 overexpression results in a significant downregulation of NADH: ubiquinone oxidoreductase activity, consequently impeding the electron transfer process and mitochondrial ATP synthesis, associated with metastasis of PCa. Collectively, our results highlight that metabolic reprogramming induced by LONP1 in PCa is closely coupled with disease progression, suggesting that targeting the LONP1-mediated cascade in the mitochondrial may provide therapeutic potential for PCa disease.

Astrocytes are critical for maintaining neuronal activity. Activation of astrocytes, occurs within minutes from ischemic stroke onset due to ischemic causes and subsequent inflammatory damage. Activated astrocytes, also known as reactive astrocytes, are divided into two different phenotypes: A1 (pro-inflammatory) and A2 (anti-inflammatory) astrocytes. A2 astrocytes support neuronal survival and promote tissue healing, while A1 astrocytes have neurotoxic effects. Thus, polarization of reactive astrocyte into A1 or A2 genotype is closely correlated with the development of cerebral ischemia/reperfusion (I/R) injury. Metabolic reprogramming is a process that various metabolic pathways upregulate in cells to balance energy, alter their phenotype, and produce building-block requirements. A1 and A2 astrocytes display different metabolic reprogramming, such as glycolysis, glutamate uptake, and glycogenolysis. Accumulating evidence suggested that manipulation of energy metabolism homeostasis can induce astrocytes to switch from A1 to A2 phenotype. This review disucss the potential factors in affecting astrocytic polarization, emphasizes metabolic reprogramming in reactive astrocytes within the pathophysiological context of cerebral I/R, and explores the relationship between metabolic reprogramming and astrocytic polarization. Importantly, we reveal that regulating metabolic reprogramming in reactive astrocytes may be a potential therapeutic target for cerebral I/R injury.

Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation and fate regulation in physiological and pathological settings, particularly in intricate conditions such as cancer. Specifically, lactate has been demonstrated to be pivotal in molding the tumor microenvironment (TME) through its effects on different cell populations. Within tumor cells, lactate impacts cell signaling pathways, augments the lactate shuttle process, boosts resistance to oxidative stress, and contributes to lactylation. In various cellular populations, the interplay between lactate and immune cells governs processes such as cell differentiation, immune response, immune surveillance, and treatment effectiveness. Furthermore, communication between lactate and stromal/endothelial cells supports basal membrane (BM) remodeling, epithelial-mesenchymal transitions (EMT), metabolic reprogramming, angiogenesis, and drug resistance. Focusing on lactate production and transport, specifically through lactate dehydrogenase (LDH) and monocarboxylate transporters (MCT), has shown promise in the treatment of cancer. Inhibitors targeting LDH and MCT act as both tumor suppressors and enhancers of immunotherapy, leading to a synergistic therapeutic effect when combined with immunotherapy. The review underscores the importance of lactate in tumor progression and provides valuable perspectives on potential therapeutic approaches that target the vulnerability of lactate metabolism, highlighting the Heel of Achilles for cancer treatment.