Cancer metabolism and dietary interventions

Metabolic remodeling is a key feature of cancer development.Knowledge of cancer metabolism has greatly expanded since the first observation of abnormal metabolism in cancer cells,the so-called Warburg effect.Malignant cells tend to modify cellular metabolism to favor specialized fermentation over the aerobic respiration usually used by most normal cells.Thus,targeted cancer therapies based on reprogramming nutrient or metabolite metabolism have received substantial attention both conceptually and in clinical practice.In particular,the management of nutrient availability is becoming more attractive in cancer treatment.In this review,we discuss recent findings on tumor metabolism and potential dietary interventions based on the specific characteristics of tumor metabolism.First,we present a comprehensive overview of changes in macronutrient metabolism.Carbohydrates,amino acids,and lipids,are rewired in the cancer microenvironment individually or systematically.Second,we summarize recent progress in cancer interventions applying different types of diets and specific nutrient restrictions in pre-clinical research or clinical trials.

Coherent Raman scattering imaging of lipid metabolism in cancer

Cancer cells dysregulate lipid metabolism to accelerate energy production and biomolecule synthesis for rapid growth.Lipid metabolism is highly dynamic and intrinsically heterogeneous at the single cell level.Although°uorescence microscopy has been commonly used for cancer research,bulky°uorescent probes can hardly label small lipid molecules without perturbing their biological activities.Such a challenge can be overcome by coherent Raman scattering(CRS)microscopy,which is capable of chemically selective,highly sensitive,submicron resolution and high-speed imaging of lipid molecules in single live cells without any labeling.Recently developed hyperspectral and multiplex CRS microscopy enables quantitative mapping of various lipid metabolites in situ.Further incorporation of CRS microscopy with Raman tags greatly increases molecular selectivity based on the distinct Raman peaks well separated from the endogenous cellular background.Owing to these unique advantages,CRS microscopy sheds new insights into the role of lipid metabolism in cancer development and progression.This review focuses on the latest applications of CRS microscopy in the study of lipid metabolism in cancer.

The emerging role and targetability of the TCA cycle in cancer metabolism

The tricarboxylic acid （TCA） cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance require- ments. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for thera- peutic interventions in various cancer types.

Cancer metabolism and tumor microenvironment:fostering each other?

The changes associated with malignancy are not only in cancer cells but also in environment in which cancer cells live.Metabolic reprogramming supports tumor cells’high demand of biogenesis for their rapid proliferation,and helps tumor cells to survive under certain genetic or environmental stresses.Emerging evidence suggests that metabolic alteration is ultimately and tightly associated with genetic changes,in particular the dysregulation of key oncogenic and tumor suppressive signaling pathways.Cancer cells activate HIF signaling even in the presence of oxygen and in the absence of growth factor stimulation.This cancer metabolic phenotype,described firstly by German physiologist Otto Warburg,ensures enhanced glycolytic metabolism for the biosynthesis of macromolecules.The conception of metabolite signaling,i.e.,metabolites are regulators of cell signaling,provides novel insights into how reactive oxygen species(ROS)and other metabolites deregulation may regulate redox homeostasis,epigenetics,and proliferation of cancer cells.Moreover,the unveiling of noncanonical functions of metabolic enzymes,such as the moonlighting functions of phosphoglycerate kinase 1(PGK1),reassures the importance of metabolism in cancer development.The metabolic,microRNAs,and ncRNAs alterations in cancer cells can be sorted and delivered either to intercellular matrix or to cancer adjacent cells to shape cancer microenvironment via media such as exosome.Among them,cancer microenvironmental cells are immune cells which exert profound effects on cancer cells.Understanding of all these processes is a prerequisite for the development of a more effective strategy to contain cancers.

Aerobic glycolysis and high level of lactate in cancer metabolism and microenvironment

Metabolic abnormalities is a hallmark of cancer.About 100 years ago,Nobel laureate Otto Heinrich Warburg first described high rate of glycolysis in cancer cells.Recently more and more novel opinions about cancer metabolism supplement to this hypothesis,consist of glucose uptake,lactic acid generation and secretion,acidification of the microenvironment and cancer immune evasion.Here we briefly review metabolic pathways generating lactate,and discuss the function of higher lactic acid in cancer microenvironments.

New insights into molecules and pathways of cancer metabolism and therapeutic implications

Cancer cells are abnormal cells that can reproduce and regenerate rapidly.They are characterized by unlimited proliferation,transformation and migration,and can destroy normal cells.To meet the needs for cell proliferation and migration,tumor cells acquire molecular materials and energy through unusual metabolic pathways as their metabolism is more vigorous than that of normal cells.Multiple carcinogenic signaling pathways eventually converge to regulate three major metabolic pathways in tumor cells,including glucose,lipid,and amino acid metabolism.The distinct metabolic signatures of cancer cells reflect that metabolic changes are indispensable for the genesis and development of tumor cells.In this review,we report the unique metabolic alterations in tumor cells which occur through various signaling axes,and present various modalities available for cancer diagnosis and clinical therapy.We further provide suggestions for the development of anti-tumor therapeutic drugs.

Cancer metabolism in gastrointestinal cancer

Cancer cells exhibit altered glucose metabolism,mitochondrial dysfunction,anaerobic glycolysis and upregulation of the pentose phosphate pathway(PPP).Recent genetic and metabolic analyses have provided insights into the molecular mechanisms of genes that are involved in the alteration of cancer metabolism and tumorigenesis.Hypoxic induced factor 1 regulates the reciprocal relationship between glycolysis and oxidative phosphorylation,and p53 also modulates the balance between the glycolytic pathway and oxidative phosphorylation.Mitochondria function in cancer differs from that in normal cells owing to mutations of mitochondrial DNA and alterations of metabolism.Overexpression of transcription factors,metabolite transporters and glycolytic enzymes is observed and associated with poor prognosis,and it may be associated with chemoradiotherapy resistance in multiple cancer cell types.The PPP plays a critical role in regulating cancer cell growth by supplying cells with ribose-5-phosphate and nicotinamide adenine dinucleotide phosphate for detoxifi cation of intra-cellular reactive oxygen species(ROS),reductive biosynthesis and ribose biogenesis.ROS levels increase during carcinogenesis owing to metabolic aberrations.This review discusses alterations of mitochondrial metabolism,anaerobic glycolysis,the PPP and control of ROS levels by the endogenous anti-oxidant system in cancer,as well as the novel small molecules targeting these enzymes or transporters that exert anti-proliferative effects.

Natural Products and Derivatives Targeting at Cancer Energy Metabolism:A Potential Treatment Strategy

In the 1920s,Dr Otto Warburg first suggested the significant difference in energy metabolism between malignant cancer cells and adjacent normal cells.Tumor cells mainly adopt the glycolysis as energy source to maintain tumor cell growth and biosynthesis under aerobic conditions.Investigation on energy metabolism pathway in cancer cells has aroused the interest of cancer researchers all around the world.In recent years,plentiful studics suggest that targeting the peculiar cancer energy metabolic pathways,including glycolysis,mitochondrial respiration,amino acid metabolism,and fatty acid oxidation may be an effective strategy to starve cancer cells by blocking essential nutrients.Natural products (NPs)are considered as the “treasure trove of small molecules drugs” and have played an extremely remarkable role in the discovery and development of anticancer drugs.And numerous NPs have been reported to act on cancer energy metabolism targets.Herein,a comprehensive overview about cancer energy metabolism targets and their natural-occurring inhibitors is prepared.

Anticancer Activities of Plant Secondary Metabolites:Rice Callus Suspension Culture as a New Paradigm

Plant natural products including alkaloids,polyphenols,terpenoids and flavonoids have been reported to exert anticancer activity by targeting various metabolic pathways.The biological pathways regulated by plant products can serve as novel drug targets.Plant natural compounds or their derivatives used for cancer treatment and some novel plant-based compounds which are used in clinical trials were discussed.Callus suspension culture with secondary metabolites can provide a continuous source of plant pharmaceuticals without time and space limitations.Previous research has shown that rice callus suspension culture can kill>95%cancer cells with no significant effect on the growth of normal cells.The role of candidate genes and metabolites which are likely to be involved in the process and their potential to serve as anticancer and anti-inflammatory agents were discussed.Large scale production of plant callus suspension culture and its constituents can be achieved using elicitors which enhance specific secondary metabolites combined with bioprocess technology.

Targeting androgen receptor-independent pathways in therapy-resistant prostate cancer

Since androgen receptor(AR)signaling is critically required for the development of prostate cancer(PCa),targeting AR axis has been the standard treatment of choice for advanced and metastatic PCa.Unfortunately,although the tumor initially responds to the therapy,treatment resistance eventually develops and the disease will progress.It is therefore imperative to identify the mechanisms of therapeutic resistance and novel molecular targets that are independent of AR signaling.Recent advances in pathology,molecular biology,genetics and genomics research have revealed novel AR-independent pathways that contribute to PCa carcinogenesis and progression.They include neuroendocrine differentiation,cell metabolism,DNA damage repair pathways and immune-mediated mechanisms.The development of novel agents targeting the non-AR mechanisms holds great promise to treat PCa that does not respond to AR-targeted therapies.

Mechanisms adopted by cancer cells to escape apoptosis–A review

Inactivation of apoptosis is the prime phenomenon in cancer development and cancer treatments.Mutations in the apoptotic pathway not only exert resistance to apoptosis and provide a survival advantage to cancer cells but also confer resistance to cancer therapies.Escaping apoptosis is the“hallmark”of cancer cells.Cancer cells can withstand many apoptotic stimuli,such as DNA damage,unfavorable environments,and cytotoxic therapies.Substantial research has been carried out and is in good progress on the various mechanisms adopted by cancer cells to evade apoptosis.This article reviews the apoptosis escape mechanisms by cancer cells,viz.apoptotic gene alterations(in few essential and accessory apoptotic genes),post-translational modifications(phosphorylation and ubiquitination of apoptotic proteins),metabolic alterations,mitochondrial alterations,immunity escape,epigenetics,cancer cell dormancy,cancer clonal theory,and reversibility of apoptosis.The review reveals that there is a wide scope for further research to address the various challenges in realizing successful cancer therapies that involve reversing the apoptotic resistance and/or inducing apoptosis in tumor cells.

The role of N-glycosylation in cancer

Despite advances in understanding the development and progression of cancer in recent years,there remains a lack of comprehensive characterization of the cancer glycoproteome.Glycoproteins play an important role in medicine and are involved in various human disease conditions including cancer.Glycan-moieties participate in fundamental cancer processes like cell signaling,invasion,angiogenesis,and metastasis.Aberrant N-glycosylation significantly impacts cancer processes and targeted therapies in clinic.Therefore,understanding N-glycosylation in a tumor is essential for comprehending disease progression and discovering anti-cancer targets and biomarkers for therapy monitoring and diagnosis.This review presents the fundamental process of protein N-glycosylation and summarizes glycosylation changes in tumor cells,including increased terminal sialylation,N-glycan branching,and corefucosylation.Also,the role of N-glycosylation in tumor signaling pathways,migration,and metabolism are discussed.Glycoproteins and glycopeptides as potential biomarkers for early detection of cancer based on site specificity have been introduced.Collectively,understanding and exploring the cancer glycoproteome,along with its role in medicine,implication in cancer and other human diseases,highlights the significance of N-glycosylation in tumor processes,necessitating further research for potential anticancer targets and biomarkers.

Aberrant LETM1 elevation dysregulates mitochondrial functions and energy metabolism and promotes lung metastasis in osteosarcoma

Osteosarcoma is a differentiation-deficient disease,and despite the unique advan-tages and great potential of differentiation therapy,there are only a few known differentia-tion inducers,and little research has been done on their targets.Cell differentiation is associated with an increase in mitochondrial content and activity.The metabolism of some tu-mor cells is characterized by impaired oxidative phosphorylation,as well as up-regulation of aerobic glycolysis and pentose phosphate pathways.Leucine-containing zipper and EF-hand transmembrane protein 1(LETM1)is involved in the maintenance of mitochondrial morphology and is closely associated with tumorigenesis and progression,as well as cancer cell stemness.We found that MG63 and 143B osteosarcoma cells overexpress LETM1 and exhibit abnormalities in mitochondrial structure and function.Knockdown of LETM1 partially restored the mitochon-drial structure and function,inhibited the pentose phosphate pathway,promoted oxidative phosphorylation,and led to osteogenic differentiation.It also inhibited spheroid cell forma-tion,proliferation,migration,and invasion in an in vitro model.When LETM1 was knocked down in vivo,there was reduced tumor formation and lung metastasis.These data suggest that mitochondria are aberrant in LETM1-overexpressing osteosarcoma cells,and knockdown of LETM1 partially restores the mitochondrial structure and function,inhibits the pentose phosphate pathway,promotes oxidative phosphorylation,and increases osteogenic differentiation,thereby reducing malignant biological behavior of the cells.

LncRNA-mediated posttranslational modifications and reprogramming of energy metabolism in cancer

Altered metabolism is a hallmark of cancer,and the reprogramming of energy metabolism has historically been considered a general phenomenon of tumors.It is well recognized that long noncoding RNAs(lncRNAs)regulate energy metabolism in cancer.However,lncRNA-mediated posttranslational modifications and metabolic reprogramming are unclear at present.In this review,we summarized the current understanding of the interactions between the alterations in cancer-associated energy metabolism and the lncRNA-mediated posttranslational modifications of metabolic enzymes,transcription factors,and other proteins involved in metabolic pathways.In addition,we discuss the mechanisms through which these interactions contribute to tumor initiation and progression,and the key roles and clinical significance of functional lncRNAs.We believe that an in-depth understanding of lncRNA-mediated cancer metabolic reprogramming can help to identify cellular vulnerabilities that can be exploited for cancer diagnosis and therapy.

Advances in regulation and function of stearoyl-CoA desaturase 1 in cancer,from bench to bed

Stearoyl-CoA desaturase 1(SCD1)converts saturated fatty acids to monounsaturated fatty acids.The expression of SCD1 is increased in many cancers,and the altered expression contributes to the proliferation,invasion,stemness and chemoresistance of cancer cells.Recently,more evidence has been reported to further support the important role of SCD1 in cancer,and the regulation mechanism of SCD1 has also been focused.Multiple factors are involved in the regulation of SCD1,including metabolism,diet,tumor microenvironment,transcription factors,non-coding RNAs,and epigenetics modification.Moreover,SCD1 is found to be involved in regulating ferroptosis resistance.Based on these findings,SCD1 has been considered as a potential target for cancer treatment.However,the resistance of SCD1 inhibition may occur in certain tumors due to tumor heterogeneity and metabolic plasticity.This review summarizes recent advances in the regulation and function of SCD1 in tumors and discusses the potential clinical application of targeting SCD1 for cancer treatment.

The role of circadian clocks in cancer:Mechanisms and clinical implications

Circadian rhythm refers to the inherent 24-h cycle oscillation of biochemical,phys-iological and behavioral functions,which is almost universal in eukaryotes.At least 14 core clock genes have been reported to form multiple chain feedback loops that confer intrinsic circadian rhythmicity onto the molecular clock.Accumulating evidence has shown that the circadian gene dysfunction resulted from single nucleotide polymorphisms(SNPs),deletions,epigenetic modification,and deregulation is strongly associated with cancer risk.In the pre-sent review,we describe the composition of circadian rhythm system.We highlight the func-tion and mechanism of clock genes in cancer pathogenesis and progression.Moreover,their potential clinical implications as prognostic biomarkers and therapeutic targets have been ad-dressed.

Connections between metabolism and epigenetic modifications in cancer

How cells sense and respond to environmental changes is still a key question.It has been identified that cellular metabolism is an important modifier of various epigenetic modifications,such as DNA methylation,histone methylation and acetylation and RNA N6-methyladenosine(m6A)methylation.This closely links the environmental nutrient availability to the maintenance of chromatin structure and gene expression,and is crucial to regulate cellular homeostasis,cell growth and differentiation.Cancer metabolic reprogramming and epigenetic alterations are widely observed,and facilitate cancer development and progression.In cancer cells,oncogenic signaling-driven metabolic reprogramming modifies the epigenetic landscape via changes in the keymetabolite levels.In this review,we briefly summarized the current evidence that the abundance of key metabolites,such as S-adenosyl methionine(SAM),acetyl-CoA,α-ketoglutarate(α-KG),2-hydroxyglutarate(2-HG),uridine diphospho-N-acetylglucosamine(UDP-GlcNAc)and lactate,affected by metabolic reprogramming plays an important role in dynamically regulating epigenetic modifications in cancer.An improved understanding of the roles of metabolic reprogramming in epigenetic regulation can contribute to uncover the underlying mechanisms of metabolic reprogramming in cancer development and identify the potential targets for cancer therapies.

Amino acid transporter SLC7A11/ xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer

Cancer cells often upregulate nutrient transporters to fulfill their increased biosynthetic and bioenergetic needs,and to maintain redox homeostasis.One nutrient transporter frequently overexpressed in human cancers is the cystine/glutamate antiporter solute carrier family 7 member 11(SLC7A11;also known as xCT).SLC7A11 promotes cystine uptake and glutathione biosynthesis,resulting in protection from oxidative stress and ferroptotic cell death.Recent studies have unexpectedly revealed that SLC7A11 also plays critical roles in glutamine metabolism and regulates the glucose and glutamine dependency of cancer cells.This review discusses the roles of SLC7A11 in regulating the anti-oxidant response and nutrient dependency of cancer cells,explores our current understanding of SLC7A11 regulation in cancer metabolism,and highlights key open questions for future studies in this emerging research area.A deeper understanding of SLC7A11 in cancer metabolism may identify new therapeutic opportunities to target this important amino acid transporter for cancer treatment.

Associations of PGK1 promoter hypomethylation and PGK1-mediated PDHK1 phosphorylation with cancer stage and prognosis:a TCGA pan-cancer analysis

Background:Cancer cells reprogram metabolism for proliferation.Phosphoglycerate kinase 1(PGK1),as a glycolytic enzyme and newly identified protein kinase,coordinates glycolysis and mitochondrial metabolism.However,the clini-cal significance of PGK1 expression and function in cancer progression is unclear.Here,we investigated the relation-ship between the progression and prognosis of multiple cancer types and PGK1 expression and its function in the mitochondrial metabolism regulation.Methods:We performed pan-cancer analyses of PGK1 mRNA level and DNA methylation in 11,908 tumor tissues and 1582 paired normal tissues across 34 cancer types in The Cancer Genome Atlas datasets.Using specific antibodies against PGK1 S203 and PDHK1 T338 phosphorylation,we performed immunohistochemistry with tissue microarray assay in additional 818 cancer cases with 619 paired normal tissues from five cancer types.Results:The PGK1 mRNA level was significantly elevated with hypomethylation in promotor regions and associated with advanced TNM stage in 15 and four cancer types,respectively.In breast carcinoma,elevated PGK1 mRNA level and promoter hypomethylation were associated with poor prognosis.Positively correlated PGK1 S203 and PDHK1 T338 phosphorylation levels were significantly associated with short overall survival(OS)in cancers of the breast,liver,lung,stomach,and esophagus and with advanced TNM stage in breast and esophageal cancers.PGK1 pS203 and PDHK1 pT338 were also independent predictors of short OS in liver,lung,and stomach cancer.Conclusions:The elevated expression,promoter hypomethylation,and phosphorylation of PGK1 and PDHK1 were related with disease progression and short OS in diverse types of cancer.PGK1 and PDHK1 phosphorylation may be potential prognostic biomarkers.

Spatial metabolomics for evaluating response to neoadjuvant therapy in non-small cell lung cancer patients

Background:The response to neoadjuvant chemotherapy(NAC)differs substantially among individual patients with non-small cell lung cancer(NSCLC).Major pathological response(MPR)is a histomorphological read-out used to assess treatment response and prognosis in patientsNSCLC afterNAC.Although spatial metabolomics is a promising tool for evaluating metabolic phenotypes,it has not yet been utilized to assess therapy responses in patients with NSCLC.We evaluated the potential application of spatial metabolomics in cancer tissues to assess the response to NAC,using a metabolic classifier that utilizes mass spectrometry imaging combined with machine learning.Methods:Resected NSCLC tissue specimens obtained after NAC(n=88)were subjected to high-resolution mass spectrometry,and these data were used to develop an approach for assessing the response to NAC in patients with NSCLC.The specificities of the generated tumor cell and stroma classifiers were validated by applying this approach to a cohort of biologically matched chemotherapy-naive patients with NSCLC(n=85).Results:The developed tumor cell metabolic classifier stratified patients into different prognostic groups with 81.6%accuracy,whereas the stroma metabolic classifier displayed 78.4%accuracy.By contrast,the accuracies of MPR and TNM staging for stratification were 62.5%and 54.1%,respectively.The combination of metabolic and MPR classifiers showed slightly lower accuracy than either individual metabolic classifier.In multivariate analysis,metabolic classifiers were the only independent prognostic factors identified(tumor:P=0.001,hazards ratio[HR]=3.823,95%confidence interval[CI]=1.716-8.514;stroma:P=0.049,HR=2.180,95%CI=1.004-4.737),whereasMPR(P=0.804;HR=0.913;95%CI=0.445-1.874)and TNM staging(P=0.078;HR=1.223;95%CI=0.977-1.550)were not independent prognostic factors.Using Kaplan-Meier survival analyses,both tumor and stroma metabolic classifiers were able to further stratify patients as NAC responders(P<0.001)and non-responders(P<0.001).Conclusions:Our findings indicate that the metabolic constitutions of both tumor cells and the stroma are valuable additions to the classical histomorphology-based assessment of tumor response.