bims-kracam 2021-07-04 papers

on K-Ras in cancer metabolism

Issue of 2021–07–04
twenty-one papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development

Transforming Growth Factor-β and Oxidative Stress in Cancer: A Crosstalk in Driving Tumor Transformation.
One-Carbon Metabolism Associated Vulnerabilities in Glioblastoma: A Review.
Tumor Microenvironment-Derived Metabolites: A Guide to Find New Metabolic Therapeutic Targets and Biomarkers.
Metabolic Reprogramming of Colorectal Cancer Cells and the Microenvironment: Implication for Therapy.
Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect.
Targeting super-enhancers reprograms glioblastoma central carbon metabolism.
A pan-cancer transcriptomic study showing tumor specific alterations in central metabolism.
Serine hydroxymethyltransferase 2: a novel target for human cancer therapy.
The Hippo Pathway: A Master Regulatory Network Important in Cancer.
Chrysin: Perspectives on Contemporary Status and Future Possibilities as Pro-Health Agent.
Asparagine: A Metabolite to Be Targeted in Cancers.
Metabolism and function of polyamines in cancer progression.
Role of Natural Bioactive and their Nanocarriers for Overcoming Oxidative Stress-Induced Cancer.
Kynurenines as a Novel Target for the Treatment of Malignancies.
VDAC1 Silencing in Cancer Cells Leads to Metabolic Reprogramming That Modulates Tumor Microenvironment.
Mitochondrial Function Are Disturbed in the Presence of the Anticancer Drug, 3-Bromopyruvate.
THE MAIN CYTOTOXIC EFFECTS OF METHYLSELENINIC ACID ON VARIOUS CANCER CELLS.
Natural Compounds as Metabolic Modulators of the Tumor Microenvironment.
Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update.
Anticancer effects of Traditional Chinese Medicine on epithelial-mesenchymal transition（EMT） in breast cancer: Cellular and molecular targets.
Cross-talks in colon cancer between RAGE/AGEs axis and inflammation/immunotherapy.

Cancers (Basel). 2021 Jun 21. pii: 3093. [Epub ahead of print]13(12):

Transforming Growth Factor-β and Oxidative Stress in Cancer: A Crosstalk in Driving Tumor Transformation.

Valeria Ramundo, Giuliana Giribaldi, Elisabetta Aldieri.

  Cancer metabolism involves different changes at a cellular level, and altered metabolic pathways have been demonstrated to be heavily involved in tumorigenesis and invasiveness. A crucial role for oxidative stress in cancer initiation and progression has been demonstrated; redox imbalance, due to aberrant reactive oxygen species (ROS) production or deregulated efficacy of antioxidant systems (superoxide dismutase, catalase, GSH), contributes to tumor initiation and progression of several types of cancer. ROS may modulate cancer cell metabolism by acting as secondary messengers in the signaling pathways (NF-kB, HIF-1α) involved in cellular proliferation and metastasis. It is known that ROS mediate many of the effects of transforming growth factor β (TGF-β), a key cytokine central in tumorigenesis and cancer progression, which in turn can modulate ROS production and the related antioxidant system activity. Thus, ROS synergize with TGF-β in cancer cell metabolism by increasing the redox imbalance in cancer cells and by inducing the epithelial mesenchymal transition (EMT), a crucial event associated with tumor invasiveness and metastases. Taken as a whole, this review is addressed to better understanding this crosstalk between TGF-β and oxidative stress in cancer cell metabolism, in the attempt to improve the pharmacological and therapeutic approach against cancer.

Keywords:  EMT; TGF-β; oxidative stress

DOI:  https://doi.org/10.3390/cancers13123093
Cancers (Basel). 2021 Jun 19. pii: 3067. [Epub ahead of print]13(12):

One-Carbon Metabolism Associated Vulnerabilities in Glioblastoma: A Review.

Kimia Ghannad-Zadeh, Sunit Das.

  Altered cell metabolism is a hallmark of cancer cell biology, and the adaptive metabolic strategies of cancer cells have been of recent interest to many groups. Metabolic reprogramming has been identified as a critical step in glial cell transformation, and the use of antimetabolites against glioblastoma has been investigated. One-carbon (1-C) metabolism and its associated biosynthetic pathways, particularly purine nucleotide synthesis, are critical for rapid proliferation and are altered in many cancers. Purine metabolism has also been identified as essential for glioma tumourigenesis. Additionally, alterations of 1-C-mediated purine synthesis have been identified as commonly present in brain tumour initiating cells (BTICs) and could serve as a phenotypic marker of cells responsible for tumour recurrence. Further research is required to elucidate mechanisms through which metabolic vulnerabilities may arise in BTICs and potential ways to therapeutically target these metabolic processes. This review aims to summarize the role of 1-C metabolism-associated vulnerabilities in glioblastoma tumourigenesis and progression and investigate the therapeutic potential of targeting this pathway in conjunction with other treatment strategies.

Keywords:  de novo purine synthesis; glioblastoma; glioma; metabolic reprogramming; metabolic treatment; one-carbon metabolism

DOI:  https://doi.org/10.3390/cancers13123067
Cancers (Basel). 2021 Jun 28. pii: 3230. [Epub ahead of print]13(13):

Tumor Microenvironment-Derived Metabolites: A Guide to Find New Metabolic Therapeutic Targets and Biomarkers.

Juan C García-Cañaveras, Agustín Lahoz.

  Metabolic reprogramming is a hallmark of cancer that enables cancer cells to grow, proliferate and survive. This metabolic rewiring is intrinsically regulated by mutations in oncogenes and tumor suppressors, but also extrinsically by tumor microenvironment factors (nutrient and oxygen availability, cell-to-cell interactions, cytokines, hormones, etc.). Intriguingly, only a few cancers are driven by mutations in metabolic genes, which lead metabolites with oncogenic properties (i.e., oncometabolites) to accumulate. In the last decade, there has been rekindled interest in understanding how dysregulated metabolism and its crosstalk with various cell types in the tumor microenvironment not only sustains biosynthesis and energy production for cancer cells, but also contributes to immune escape. An assessment of dysregulated intratumor metabolism has long since been exploited for cancer diagnosis, monitoring and therapy, as exemplified by 18F-2-deoxyglucose positron emission tomography imaging. However, the efficient delivery of precision medicine demands less invasive, cheaper and faster technologies to precisely predict and monitor therapy response. The metabolomic analysis of tumor and/or microenvironment-derived metabolites in readily accessible biological samples is likely to play an important role in this sense. Here, we review altered cancer metabolism and its crosstalk with the tumor microenvironment to focus on energy and biomass sources, oncometabolites and the production of immunosuppressive metabolites. We provide an overview of current pharmacological approaches targeting such dysregulated metabolic landscapes and noninvasive approaches to characterize cancer metabolism for diagnosis, therapy and efficacy assessment.

Keywords:  LC-MS; MRI; MRS; biomarkers; cancer metabolism; cancer therapy; imaging; metabolic inhibitors; metabolomics; oncometabolites

DOI:  https://doi.org/10.3390/cancers13133230
Int J Mol Sci. 2021 Jun 10. pii: 6262. [Epub ahead of print]22(12):

Metabolic Reprogramming of Colorectal Cancer Cells and the Microenvironment: Implication for Therapy.

Miljana Nenkov, Yunxia Ma, Nikolaus Gaßler, Yuan Chen.

  Colorectal carcinoma (CRC) is one of the most frequently diagnosed carcinomas and one of the leading causes of cancer-related death worldwide. Metabolic reprogramming, a hallmark of cancer, is closely related to the initiation and progression of carcinomas, including CRC. Accumulating evidence shows that activation of oncogenic pathways and loss of tumor suppressor genes regulate the metabolic reprogramming that is mainly involved in glycolysis, glutaminolysis, one-carbon metabolism and lipid metabolism. The abnormal metabolic program provides tumor cells with abundant energy, nutrients and redox requirements to support their malignant growth and metastasis, which is accompanied by impaired metabolic flexibility in the tumor microenvironment (TME) and dysbiosis of the gut microbiota. The metabolic crosstalk between the tumor cells, the components of the TME and the intestinal microbiota further facilitates CRC cell proliferation, invasion and metastasis and leads to therapy resistance. Hence, to target the dysregulated tumor metabolism, the TME and the gut microbiota, novel preventive and therapeutic applications are required. In this review, the dysregulation of metabolic programs, molecular pathways, the TME and the intestinal microbiota in CRC is addressed. Possible therapeutic strategies, including metabolic inhibition and immune therapy in CRC, as well as modulation of the aberrant intestinal microbiota, are discussed.

Keywords:  CRC therapy; colorectal cancer; intestinal microbiota; metabolism; the tumor microenvironment

DOI:  https://doi.org/10.3390/ijms22126262
Int J Mol Sci. 2021 Jun 08. pii: 6173. [Epub ahead of print]22(12):

Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect.

So-Hee Kim, Kwang-Hyun Baek.

  Cancer is a disorder of cell growth and proliferation, characterized by different metabolic pathways within normal cells. The Warburg effect is a major metabolic process in cancer cells that affects the cellular responses, such as proliferation and apoptosis. Various signaling factors down/upregulate factors of the glycolysis pathway in cancer cells, and these signaling factors are ubiquitinated/deubiquitinated via the ubiquitin-proteasome system (UPS). Depending on the target protein, DUBs act as both an oncoprotein and a tumor suppressor. Since the degradation of tumor suppressors and stabilization of oncoproteins by either negative regulation by E3 ligases or positive regulation of DUBs, respectively, promote tumorigenesis, it is necessary to suppress these DUBs by applying appropriate inhibitors or small molecules. Therefore, we propose that the DUBs and their inhibitors related to the Warburg effect are potential anticancer targets.

Keywords:  anaerobic glycolysis; anticancer; hypoxia; small molecules; ubiquitin–proteasome system (UPS)

DOI:  https://doi.org/10.3390/ijms22126173
Oncotarget. 2021 Jun 22. 12(13): 1309-1313

Targeting super-enhancers reprograms glioblastoma central carbon metabolism.

Trang T T Nguyen, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin.

  The concept that tumor cells demand a distinct form of metabolism was appreciated almost a century ago when the German biochemist Otto Warburg realized that tumor cells heavily utilize glucose and produce lactic acid while relatively reducing oxidative metabolism. How this phenomenon is orchestrated and regulated is only partially understood and seems to involve certain transcription factors, including c-Myc, HIF1A and others. The epigenome eintails the posttranslational modification of histone proteins which in turn are involved in regulation of transcription. Recently, it was found that cis-regulatory elements appear to facilitate the Warburg effects since several genes encoding for glycolysis and associated pathways are surrounded by enhancer/super-enhancer regions. Disruption of these regions by FDA-approved HDAC inhibitors suppressed the transcription of these genes and elicited a reversal of the Warburg effect with activation of transcription factors facilitating oxidative energy metabolism with increases in transcription factors that are part of the PPARA family. Therefore, combined targeting of HDACs and oxidative metabolism suppressed tumor growth in patient-derived xenograft models of solid tumors, including glioblastoma.

Keywords:  HDAC-inhibitor; c-Myc; fatty acid oxidation; glioblastoma; metabolism

DOI:  https://doi.org/10.18632/oncotarget.27938
Sci Rep. 2021 Jul 01. 11(1): 13637

A pan-cancer transcriptomic study showing tumor specific alterations in central metabolism.

Ilir Sheraj, N Tulin Guray, Sreeparna Banerjee.

Recently, there has been a resurgence of interest in metabolic rewiring of tumors to identify clinically relevant genes. However, most of these studies have had either focused on individual tumors, or are too general, providing a broad outlook on overall changes. In this study, we have first curated an extensive list of genes encoding metabolic enzymes and metabolite transporters relevant to carbohydrate, fatty acid and amino acid oxidation and biosynthesis. Next, we have used publicly available transcriptomic data for 20 different tumor types from The Cancer Genome Atlas Network (TCGA) and focused on differential expression of these genes between tumor and adjacent normal tissue. Our study revealed major transcriptional alterations in genes that are involved in central metabolism. Most tumors exhibit upregulation in carbohydrate and amino acid transporters, increased glycolysis and pentose phosphate pathway, and decreased fatty acid and amino acid oxidation. On the other hand, the expression of genes of the tricarboxylic acid cycle, anaplerotic reactions and electron transport chain differed between tumors. Although most transcriptomic alterations were conserved across many tumor types suggesting the initiation of common regulatory programs, expression changes unique to specific tumors were also identified, which can provide gene expression fingerprints as potential biomarkers or drug targets. Our study also emphasizes the value of transcriptomic data in the deeper understanding of metabolic changes in diseases.

DOI: https://doi.org/10.1038/s41598-021-93003-3
Invest New Drugs. 2021 Jul 03.

Serine hydroxymethyltransferase 2: a novel target for human cancer therapy.

Min Xie, Dong-Sheng Pei.

  Serine and glycine are the primary sources of one-carbon units that are vital for cell proliferation. Their abnormal metabolism is known to be associated with cancer progression. As the key enzyme of serine metabolism, Serine Hydroxymethyltransferase 2 (SHMT2) has been a research hotspot in recent years. SHMT2 is a PLP-dependent tetrameric enzyme that catalyzes the reversible transition from serine to glycine, thus promoting the production of one-carbon units that are indispensable for cell growth and regulation of the redox and epigenetic states of cells. Under a hypoxic environment, SHMT2 can be upregulated and could promote the generation of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione for maintaining the redox balance. Accumulating evidence confirmed that SHMT2 facilitates cell proliferation and tumor growth and is tightly associated with poor prognosis. In this review, we present insights into the function and research development of SHMT2 and summarize the possible molecular mechanisms of SHMT2 in promoting tumor growth, in the hope that it could provide clues to more effective clinical treatment of cancer.

Keywords:  Cancer; Hypoxic environment; SHMT2; Warburg effect

DOI:  https://doi.org/10.1007/s10637-021-01144-z
Cells. 2021 Jun 07. pii: 1416. [Epub ahead of print]10(6):

The Hippo Pathway: A Master Regulatory Network Important in Cancer.

Qiuping Liu, Xiaomeng Liu, Guanbin Song.

  The Hippo pathway is pervasively activated and has been well recognized to play critical roles in human cancer. The deregulation of Hippo signaling involved in cancer development, progression, and resistance to cancer treatment have been confirmed in several human cancers. Its biological significance and deregulation in cancer have drawn increasing interest in the past few years. A fundamental understanding of the complexity of the Hippo pathway in cancer is crucial for improving future clinical interventions and therapy for cancers. In this review, we try to clarify the complex regulation and function of the Hippo signaling network in cancer development, including its role in signal transduction, metabolic regulation, and tumor development, as well as tumor therapies targeting the Hippo pathway.

Keywords:  Hippo pathway; cancer therapy; metabolic regulation; signal transduction

DOI:  https://doi.org/10.3390/cells10061416
Nutrients. 2021 Jun 14. pii: 2038. [Epub ahead of print]13(6):

Chrysin: Perspectives on Contemporary Status and Future Possibilities as Pro-Health Agent.

Monika Stompor-Gorący, Agata Bajek-Bil, Maciej Machaczka.

  Chrysin belongs to the group of natural polyphenols. It can be found, among others, in honey, propolis and fruits and has a wide range of biological activities, including the prevention of oxidative stress, inflammation, neurodegeneration and carcinogenesis. Being a part of the human diet, chrysin is considered to be a promising compound to be used in the prevention of many diseases, including cancers, diabetes and neurodegenerative diseases such as Alzheimer's or Parkinson's. Nevertheless, due to the low solubility of chrysin in water and under physiological conditions, its bioavailability is low. For this reason, attempts at its functionalization have been undertaken, aiming to increase its absorption and thus augment its in vivo therapeutic efficacy. The aim of this review is to summarize the most recent research on chrysin, including its sources, metabolism, pro-health effects and the effects of its functionalization on biological activity and pharmacological efficacy, evaluated both in vitro and in vivo.

Keywords:  anticancer activity; antioxidants; chrysin; immunomodulators; neuroprotection

DOI:  https://doi.org/10.3390/nu13062038
Metabolites. 2021 Jun 19. pii: 402. [Epub ahead of print]11(6):

Asparagine: A Metabolite to Be Targeted in Cancers.

Jie Jiang, Sandeep Batra, Ji Zhang.

  Amino acids play central roles in cancer progression beyond their function as building blocks for protein synthesis. Thus, targeting amino acid acquisition and utilization has been proved to be therapeutically beneficial in various pre-clinical models. In this regard, depletion of circulating asparagine, a nonessential amino acid, by L-asparaginase has been used in treating pediatric acute lymphoblastic leukemia (ALL) for decades. Of interest, unlike most solid tumor cells, ALL cells lack the ability to synthesize their own asparagine de novo effectively. However, only until recently, growing evidence suggests that solid tumor cells strive to acquire adequate amounts of asparagine to support tumor progression. This process is subjected to the regulation at various levels, including oncogenic signal, tumor-niche interaction, intratumor heterogeneity and dietary accessibility. We will review the literature on L-asparaginase-based therapy as well as recent understanding of asparagine metabolism in solid tumor progression, with the hope of shedding light into a broader cancer therapeutic strategy by perturbing its acquisition and utilization.

Keywords:  ATF4; GCN2; L-asparaginase; acute lymphoblastic leukemia; asparagine; asparagine synthetase; mTORC1; metabolic adaptation; stress response

DOI:  https://doi.org/10.3390/metabo11060402
Cancer Lett. 2021 Jun 26. pii: S0304-3835(21)00305-0. [Epub ahead of print]

Metabolism and function of polyamines in cancer progression.

Ita Novita Sari, Tania Setiawan, Kwang Seock Kim, Yoseph Toni Wijaya, Kae Won Cho, Hyog Young Kwon.

  Polyamines are essential for the proliferation, differentiation, and development of eukaryotes. They include spermine, spermidine, and the diamine precursor putrescine, and are low-molecular-weight, organic polycations with more than two amino groups. Their intracellular concentrations are strictly maintained within a specific physiological range through several regulatory mechanisms in normal cells. In contrast, polyamine metabolism is dysregulated in many neoplastic states, including cancer. In various types of cancer, polyamine levels are elevated, and crosstalk occurs between polyamine metabolism and oncogenic pathways, such as mTOR and RAS pathways. Thus, polyamines might have potential as therapeutic targets in the prevention and treatment of cancer. The molecular mechanisms linking polyamine metabolism to carcinogenesis must be unraveled to develop novel inhibitors of polyamine metabolism. This overview describes the nature of polyamines, their association with carcinogenesis, the development of polyamine inhibitors and their potential, and the findings of clinical trials.

Keywords:  Cancer; Metabolism; Polyamine; Therapy

DOI:  https://doi.org/10.1016/j.canlet.2021.06.020
Curr Med Chem. 2021 Jun 28.

Role of Natural Bioactive and their Nanocarriers for Overcoming Oxidative Stress-Induced Cancer.

Saurabh Mittal, Muhammad Usama Ashhara, Alka Ahuja, Javed Ali, Sanjula Baboota.

   BACKGROUND: Oxidative stress and free radicals are harmful to human health. Reactive oxygen species are the major source of oxidative stress and are one of the major causes of cancer development. Cancer is one of the leading causes of death worldwide. Prolong use of synthetic chemotherapeutic due to their low bioavailability leads to systemic toxic side effects. To surmount this problem, the use of antioxidants is recommended as they have the ability to counteract oxidative stress and mitigate its effects on human health. They inhibit various pathways that are involved with the initiation and progression of cancer. Various nanoformulations have been used to deliver these antioxidants (curcumin, mangiferin, quercetin) in the treatment of various cancer for overcoming oxidative stress.
OBJECTIVE: The main focus of this review article is to illustrate various studies performed using nanocarriers of natural bioactives to overcome oxidative stress and the cancer associated with it. It also describes the pathways associated with the induction, initiation, and progression of cancer due to reactive oxidative species.
METHODS: Research articles that focused on the use of natural bioactives and their nanoformulations for the treatment of various cancers induced due to oxidative stress were collected from various search engines like PubMed, Science Direct, and Google Scholar, using keywords like oxidative stress, antioxidants, cancers, ROS, etc. Conclusion: Natural bioactives have shown great potential in overcoming oxidative stress for the treatment of various cancers, yet extensive research is required so that these antioxidants and their nanocarriers can be used for the welfare of mankind in the treatment of various cancers in the near future.

Keywords:  cancer; nanoformulations; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.2174/0929867328666210628141550
Pharmaceuticals (Basel). 2021 Jun 23. pii: 606. [Epub ahead of print]14(7):

Kynurenines as a Novel Target for the Treatment of Malignancies.

Adrian Mor, Anna Tankiewicz-Kwedlo, Dariusz Pawlak.

  Malignancies are unquestionably a significant public health problem. Their effective treatment is still a big challenge for modern medicine. Tumors have developed a wide range of mechanisms to evade an immune and therapeutic response. As a result, there is an unmet clinical need for research on solutions aimed at overcoming this problem. An accumulation of tryptophan metabolites belonging to the kynurenine pathway can enhance neoplastic progression because it causes the suppression of immune system response against cancer cells. They are also involved in the development of the mechanisms responsible for the resistance to antitumor therapy. Kynurenine belongs to the most potent immunosuppressive metabolites of this pathway and has a significant impact on the development of malignancies. This fact prompted researchers to assess whether targeting the enzymes responsible for its synthesis could be an effective therapeutic strategy for various cancers. To date, numerous studies, both preclinical and clinical, have been conducted on this topic, especially regarding the inhibition of indoleamine 2,3-dioxygenase activity and their results can be considered noteworthy. This review gathers and systematizes the knowledge about the role of the kynurenine pathway in neoplastic progression and the findings regarding the usefulness of modulating its activity in anticancer therapy.

Keywords:  cancer; cancer treatment; enzyme inhibitors; immune escape; indoleamine 2,3-dioxygenase; kynurenine; kynurenine pathway; tryptophan; tryptophan 2,3-dioxygenase

DOI:  https://doi.org/10.3390/ph14070606
Cancers (Basel). 2021 Jun 07. pii: 2850. [Epub ahead of print]13(11):

VDAC1 Silencing in Cancer Cells Leads to Metabolic Reprogramming That Modulates Tumor Microenvironment.

Erez Zerbib, Tasleem Arif, Anna Shteinfer-Kuzmine, Vered Chalifa-Caspi, Varda Shoshan-Barmatz.

  The tumor microenvironment (TME) plays an important role in cell growth, proliferation, migration, immunity, malignant transformation, and apoptosis. Thus, better insight into tumor-host interactions is required. Most of these processes involve the metabolic reprogramming of cells. Here, we focused on this reprogramming in cancerous cells and its effect on the TME. A major limitation in the study of tumor-host interactions is the difficulty in separating cancerous from non-cancerous signaling pathways within a tumor. Our strategy involved specifically silencing the expression of VDAC1 in the mitochondria of human-derived A549 lung cancer xenografts in mice, but not in the mouse-derived cells of the TME. Next-generation sequencing (NGS) analysis allows distinguishing the human or mouse origin of genes, thus enabling the separation of the bidirectional cross-talk between the TME and malignant cells. We demonstrate that depleting VDAC1 in cancer cells led to metabolic reprogramming, tumor regression, and the disruption of tumor-host interactions. This was reflected in the altered expression of a battery of genes associated with TME, including those involved in extracellular matrix organization and structure, matrix-related peptidases, angiogenesis, intercellular interacting proteins, integrins, and growth factors associated with stromal activities. We show that metabolic rewiring upon mitochondrial VDAC1 silencing in cancer cells affected several components of the TME, such as structural protein matrix metalloproteinases and Lox, and elicited a stromal response resembling the reaction to a foreign body in wound healing. As tumor progression requires a cooperative interplay between the host and cancer cells, and the ECM is intensively remodeled during cancer progression, VDAC1 depletion induced metabolic reprogramming that targeted both tumor cells and resulted in the alteration of the whole spectrum of TME-related genes, affecting the reciprocal feedback between ECM molecules, host cells, and cancer cells. Thus, VDAC1 depletion using si-VDAC1 represents therapeutic potential, inhibiting cancer cell proliferation and also inducing the modulation of TME components, which influences cancer progression, migration, and invasion.

Keywords:  VDAC1; metabolism; mitochondria; reprogramming; siRNA; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers13112850
Int J Mol Sci. 2021 Jun 21. pii: 6640. [Epub ahead of print]22(12):

Mitochondrial Function Are Disturbed in the Presence of the Anticancer Drug, 3-Bromopyruvate.

Magdalena Cal, Irwin Matyjaszczyk, Karolina Filik, Rafał Ogórek, Young Ko, Stanisław Ułaszewski.

  3-bromopuryvate (3-BP) is a compound with unique antitumor activity. It has a selective action against tumor cells that exhibit the Warburg effect. It has been proven that the action of 3-BP is pleiotropic: it acts on proteins, glycolytic enzymes, reduces the amount of ATP, induces the formation of ROS (reactive oxygen species), and induces nuclear DNA damage. Mitochondria are important organelles for the proper functioning of the cell. The production of cellular energy (ATP), the proper functioning of the respiratory chain, or participation in the production of amino acids are one of the many functions of mitochondria. Here, for the first time, we show on the yeast model that 3-BP acts in the eukaryotic cell also by influence on mitochondria and that agents inhibiting mitochondrial function can potentially be used in cancer therapy with 3-BP. We show that cells with functional mitochondria are more resistant to 3-BP than rho0 cells. Using an MTT assay (a colorimetric assay for assessing cell metabolic activity), we demonstrated that 3-BP decreased mitochondrial activity in yeast in a dose-dependent manner. 3-BP induces mitochondrial-dependent ROS generation which results in ∆sod2, ∆por1, or ∆gpx1 mutant sensitivity to 3-BP. Probably due to ROS mtDNA lesions rise during 3-BP treatment. Our findings may have a significant impact on the therapy with 3-BP.

Keywords:  3-bromopyruvate; mitochondria; mtDNA damage; oxidative stress; superoxide generation; yeast

DOI:  https://doi.org/10.3390/ijms22126640
Int J Mol Sci. 2021 Jun 21. pii: 6614. [Epub ahead of print]22(12):

THE MAIN CYTOTOXIC EFFECTS OF METHYLSELENINIC ACID ON VARIOUS CANCER CELLS.

Elena G Varlamova, Egor A Turovsky.

  Studies of recent decades have repeatedly demonstrated the cytotoxic effect of selenium-containing compounds on cancer cells of various origins. Particular attention in these studies is paid to methylseleninic acid, a widespread selenium-containing compound of organic nature, for several reasons: it has a selective cytotoxic effect on cancer cells, it is cytotoxic in small doses, it is able to generate methylselenol, excluding the action of the enzyme β-lyase. All these qualities make methylseleninic acid an attractive substrate for the production of anticancer drugs on its basis with a well-pronounced selective effect. However, the studies available to date indicate that there is no strictly specific molecular mechanism of its cytotoxic effect in relation to different cancer cell lines and cancer models. This review contains generalized information on the dose- and time-dependent regulation of the toxic effect of methylseleninic acid on the proliferative properties of a number of cancer cell lines. In addition, special attention in this review is paid to the influence of this selenium-containing compound on the regulation of endoplasmic reticulum stress and on the expression of seven selenoproteins, which are localized in the endoplasmic reticulum.

Keywords:  cancer; cytotoxicity; methylseleninic acid; selenoproteins

DOI:  https://doi.org/10.3390/ijms22126614
Molecules. 2021 Jun 08. pii: 3494. [Epub ahead of print]26(12):

Natural Compounds as Metabolic Modulators of the Tumor Microenvironment.

Ana S Dias, Luisa Helguero, Catarina R Almeida, Iola F Duarte.

  The tumor microenvironment (TME) is a heterogenous assemblage of malignant and non-malignant cells, including infiltrating immune cells and other stromal cells, together with extracellular matrix and a variety of soluble factors. This complex and dynamic milieu strongly affects tumor differentiation, progression, immune evasion, and response to therapy, thus being an important therapeutic target. The phenotypic and functional features of the various cell types present in the TME are largely dependent on their ability to adopt different metabolic programs. Hence, modulating the metabolism of the cells in the TME, and their metabolic crosstalk, has emerged as a promising strategy in the context of anticancer therapies. Natural compounds offer an attractive tool in this respect as their multiple biological activities can potentially be harnessed to '(re)-educate' TME cells towards antitumoral roles. The present review discusses how natural compounds shape the metabolism of stromal cells in the TME and how this may impact tumor development and progression.

Keywords:  cancer; metabolic modulation; metabolism; natural compounds; phytochemicals; stromal cells; tumor microenvironment

DOI:  https://doi.org/10.3390/molecules26123494
Int J Mol Sci. 2021 Jun 19. pii: 6587. [Epub ahead of print]22(12):

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update.

Philippe Icard, Antoine Coquerel, Zherui Wu, Joseph Gligorov, David Fuks, Ludovic Fournel, Hubert Lincet, Luca Simula.

  Citrate plays a central role in cancer cells' metabolism and regulation. Derived from mitochondrial synthesis and/or carboxylation of α-ketoglutarate, it is cleaved by ATP-citrate lyase into acetyl-CoA and oxaloacetate. The rapid turnover of these molecules in proliferative cancer cells maintains a low-level of citrate, precluding its retro-inhibition on glycolytic enzymes. In cancer cells relying on glycolysis, this regulation helps sustain the Warburg effect. In those relying on an oxidative metabolism, fatty acid β-oxidation sustains a high production of citrate, which is still rapidly converted into acetyl-CoA and oxaloacetate, this latter molecule sustaining nucleotide synthesis and gluconeogenesis. Therefore, citrate levels are rarely high in cancer cells. Resistance of cancer cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), is frequently sustained by aerobic glycolysis and its key oncogenic drivers, such as Ras and its downstream effectors MAPK/ERK and PI3K/Akt. Remarkably, in preclinical cancer models, the administration of high doses of citrate showed various anti-cancer effects, such as the inhibition of glycolysis, the promotion of cytotoxic drugs sensibility and apoptosis, the neutralization of extracellular acidity, and the inhibition of tumors growth and of key signalling pathways (in particular, the IGF-1R/AKT pathway). Therefore, these preclinical results support the testing of the citrate strategy in clinical trials to counteract key oncogenic drivers sustaining cancer development and resistance to anti-cancer therapies.

Keywords:  ACLY; Warburg effect; cancer cells; citrate; resistance to therapies

DOI:  https://doi.org/10.3390/ijms22126587
Eur J Pharmacol. 2021 Jun 29. pii: S0014-2999(21)00428-3. [Epub ahead of print] 174275

Anticancer effects of Traditional Chinese Medicine on epithelial-mesenchymal transition（EMT） in breast cancer: Cellular and molecular targets.

Yiran Lu, Yu Ding, Jiahui Wei, Song He, Xinmiao Liu, Huihao Pan, Bao Yuan, Qing Liu, Jiabao Zhang.

  Breast cancer is a malignant epithelial tumor of ductal or lobular origin. Breast cancer remains the most frequently diagnosed invasive cancer in women and is the leading cause of cancer-associated mortality worldwide. Epithelial-mesenchymal transition (EMT), a phenotypic process of conversion from epithelial to mesenchymal cells, allows tumor cells to acquire infiltration and metastasization properties. Therapies directed at pathways, which are primarily involved in malignant transformation, can lead to clinical implications. In recent years, EMT has gained increasing attention as a potential therapeutic target in cancer therapy. Moreover, for the past few decades, increasing numbers of studies have suggested that Traditional Chinese Medicine(TCM) compounds can significantly inhibit the growth and development of breast cancer cells through the inhibition of EMT in breast cancer cells. This review discusses some essential signaling pathways associated with EMT and summarizes the effects and mechanism of TCM components on that inhibit EMT in breast cancer therapy.

Keywords:  Breast cancer; Epithelial-mesenchymal transition; Medicine; Therapy

DOI:  https://doi.org/10.1016/j.ejphar.2021.174275
Oncotarget. 2021 Jun 22. 12(13): 1281-1295

Cross-talks in colon cancer between RAGE/AGEs axis and inflammation/immunotherapy.

Annachiara Mollace, Maria Laura Coluccio, Giuseppe Donato, Vincenzo Mollace, Natalia Malara.

  The tumour microenvironment is the result of the activity of many types of cells in various metabolic states, whose metabolites are shared between cells. This cellular complexity results in an availability profile of nutrients and reactive metabolites such as advanced glycation end products (AGE). The tumour microenvironment is not favourable to immune cells due to hypoxia and for the existence of significant competition between various types of cells for a limited nutrient pool. However, it is now known that cancer cells can influence the host's immune reaction through the expression and secretion of numerous molecules. The microenvironment can therefore present itself in different patterns that contribute to shaping immune surveillance. Colorectal cancer (CRC) is one of the most important causes of death in cancer patients. Recently, immunotherapy has begun to give encouraging results in some groups of patients suffering from this neoplasm. The analysis of literature data shows that the RAGE (Receptor for advanced glycation end products) and its numerous ligands contribute to connect the energy metabolic pathway, which appears prevalently disconnected by mitochondrial running, with the immune reaction, conditioned by local microbiota and influencing tumour growth. Understanding how metabolism in cancer and immune cells shapes response and resistance to therapy, will provide novel potential strategies to increase both the number of tumour types treated by immunotherapy and the rate of immunotherapy response. The analysis of literature data shows that an immunotherapy approach based on the knowledge of RAGE and its ligands is not only possible, but also desirable in the treatment of CRC.

Keywords:  AGEs; RAGE; Warburg effect; colon cancer; microenvironment

DOI:  https://doi.org/10.18632/oncotarget.27990