bims-kracam 2021-08-29 papers

on K-Ras in cancer metabolism

Issue of 2021‒08‒29
twenty-two papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development

Blockade of mutant RAS oncogenic signaling with a special emphasis on KRAS.
Targeting triglyceride metabolism for colorectal cancer prevention and therapy.
Metformin and Cancer Glucose Metabolism: At the Bench or at the Bedside?
Protein networks linking Warburg and reverse Warburg effects to cancer cell metabolism.
Understanding the Therapeutic Potential of Ascorbic Acid in the Battle to Overcome Cancer.
TNBC: Potential Targeting of Multiple Receptors for a Therapeutic Breakthrough, Nanomedicine, and Immunotherapy.
The role of 5-HT metabolism in cancer.
Pathophysiological Roles of Histamine Receptors in Cancer Progression: Implications and Perspectives as Potential Molecular Targets.
Essential amino acid metabolism-related molecular classification in triple-negative breast cancer.
A Root in Synapsis and the Other One in the Gut Microbiome-Brain Axis: Are the Two Poles of Ketogenic Diet Enough to Challenge Glioblastoma?
Ferroptosis-Related Genes in Lung Adenocarcinoma: Prognostic Signature and Immune, Drug Resistance, Mutation Analysis.
Role of Phytonutrients in Nutrigenetics and Nutrigenomics Perspective in Curing Breast Cancer.
Epithelial to Mesenchymal Transition in Patients with Pancreatic Ductal Adenocarcinoma: State-of-the-Art and Therapeutic Opportunities.
Glucose Transporters as a Target for Anticancer Therapy.
The pleiotropic functions of autophagy in metastasis.
A comprehensive review on Chrysin: Emphasis on Molecular targets, Pharmacological actions and Bio-pharmaceutical aspects.
The Involvement of Natural Polyphenols in the Chemoprevention of Cervical Cancer.
Identification of Novel Metabolism-Associated Subtypes for Pancreatic Cancer to Establish an Eighteen-Gene Risk Prediction Model.
The Effect of Oxygen and Micronutrient Composition of Cell Growth Media on Cancer Cell Bioenergetics and Mitochondrial Networks.
Metabolic Enzymes Function as Epigenetic Modulators: A Trojan Horse for Chromatin Regulation and Gene Expression.
Metabolite Biomarkers of Response (BoRs): Towards a fingerprint for the evolution of metastatic breast cancer.
An overview on the biological activity and anti-cancer mechanism of lovastatin.

Pharmacol Res. 2021 Aug 24. pii: S1043-6618(21)00390-X. [Epub ahead of print] 105806

Blockade of mutant RAS oncogenic signaling with a special emphasis on KRAS.

Robert Roskoski.

  RAS proteins (HRAS, KRAS, NRAS) participate in many physiological signal transduction processes related to cell growth, division, and survival. The RAS proteins are small (188/189 amino acid residues) and they function as GTPases. These proteins toggle between inactive and functional forms; the conversion of inactive RAS-GDP to active RAS-GTP as mediated by guanine nucleotide exchange factors (GEFs) turns the switch on and the intrinsic RAS-GTPase activity stimulated by the GTPase activating proteins (GAPs) turns the switch off. RAS is upstream to the RAS-RAF-MEK-ERK and the PI3-kinase-AKT signaling modules. Importantly, the overall incidence of RAS mutations in all cancers is about 19% and RAS mutants have been a pharmacological target for more than three decades. About 84% of all RAS mutations involve KRAS. Except for the GTP/GDP binding site, the RAS proteins lack other deep surface pockets thereby hindering efforts to identify high-affinity antagonists; thus, they have been considered to be undruggable. KRAS mutations frequently occur in lung, colorectal, and pancreatic cancers, the three most deadly cancers in the United States. Studies within the last decade demonstrated that the covalent modification of KRAS C12, which accounts for about 10% of all RAS mutations, led to the discovery of an adjacent pocket (called the switch II pocket) that accommodated a portion of the drug. This led to the development of sotorasib as a second-line treatment of KRASG12C mutant non-small cell lung cancer. Considerable effort also has been expended to develop MAP kinase and PI3-kinase pathway inhibitors as indirect RAS antagonists.

Keywords:  Adagrasib (PubChem CID: 138611145); Belvarafenib (PubChem CID: 89655386); Buparlisib (PubChem CID: 16654980); Cancer mutations; Lifirafenib (PubChem CID: 89670174); MAP kinase signaling pathway; Naporafenib (PubChem CID: 90456533); Non-small cell lung cancer; PI3-kinase signaling pathway; Pancreatic cancer; Pictilisib (PubChem CID: 17755052); RO5126766 (PubChem CID: 16719221); Sotorasib (PubChem CID: 137278711); Targeted covalent inhibitors; Tipifarnib (PubChem CID: 159324); Ulixertinib (PubChem CID: 11719003)

DOI:  https://doi.org/10.1016/j.phrs.2021.105806
Curr Drug Targets. 2021 Aug 24.

Targeting triglyceride metabolism for colorectal cancer prevention and therapy.

Nagendra Yarla, Venkateshwar Madka, Chinthalapally Rao.

  BACKGROUND: Triglycerides (TG) are one of the major constituents of body fat and energy reservoir, which consist of an ester derived from glycerol and three free fatty acids. TG lipase, monoacylglycerol lipase, fatty acid synthase, and HMG-CoA reductase are some of the key enzymes related to TG metabolism, and their roles in colorectal cancer (CRC) initiation and progression are under investigation. <P> Methods: The literature search was performed based on various published papers, mostly on triglyceride metabolism relevant to CRC in PubMed, Google Scholar and other search engines. The gene expression profiling of some of the TG metabolic pathway mediators was performed by transcriptomic and/or proteomic data from The Cancer Genome Atlas (TCGA) database using R program and cBioportal software. <P> Results and discussion: Accumulating pieces of evidence suggest that TG profiling may be used as a biomarker for the diagnosis and/or prognosis of CRC. Dysregulation of TG metabolism is associated with the initiation and progression of CRC. Most of the TG anabolic pathway mediators are overexpressed and/or overactivated during CRC tumorigenesis, while most TG catabolic pathway mediators are downregulated and/or inactivated based on literature search and correlated with TCGA data. Metabolic enzymes of TG and FAs metabolic pathways are involved in CRC tumor growth survival and metastasis. <P> Conclusion: Overall studies from the previous literature and our TCGA data analysis demonstrated that the area of research on TG-associated lipid metabolic pathways holds great promise and warranted detailed investigations in this area for the implementation of novel preventive and therapeutic strategies against CRC.

Keywords:  Drug targets; Triglyceride metabolism; chemoprevention; colorectal cancer; metabolic enzymes

DOI:  https://doi.org/10.2174/1389450122666210824150012
Biomolecules. 2021 Aug 18. pii: 1231. [Epub ahead of print]11(8):

Metformin and Cancer Glucose Metabolism: At the Bench or at the Bedside?

Cecilia Marini, Vanessa Cossu, Matteo Bauckneht, Francesco Lanfranchi, Stefano Raffa, Anna Maria Orengo, Silvia Ravera, Silvia Bruno, Gianmario Sambuceti.

  Several studies reported that metformin, the most widely used drug for type 2 diabetes, might affect cancer aggressiveness. The biguanide seems to directly impair cancer energy asset, with the consequent phosphorylation of AMP-activated protein kinase (AMPK) inhibiting cell proliferation and tumor growth. This action is most often attributed to a well-documented blockage of oxidative phosphorylation (OXPHOS) caused by a direct interference of metformin on Complex I function. Nevertheless, several other pleiotropic actions seem to contribute to the anticancer potential of this biguanide. In particular, in vitro and in vivo experimental studies recently documented that metformin selectively inhibits the uptake of 2-[18F]-Fluoro-2-Deoxy-D-Glucose (FDG), via an impaired catalytic function of the enzyme hexose-6P-dehydrogenase (H6PD). H6PD triggers a still largely uncharacterized pentose-phosphate pathway (PPP) within the endoplasmic reticulum (ER) that has been found to play a pivotal role in feeding the NADPH reductive power for both cellular proliferation and antioxidant responses. Regardless of its exploitability in the clinical setting, this metformin action might configure the ER metabolism as a potential target for innovative therapeutic strategies in patients with solid cancers and potentially modifies the current interpretative model of FDG uptake, attributing PET/CT capability to predict cancer aggressiveness to the activation of H6PD catalytic function.

Keywords:  FDG PET/CT imaging; cancer therapy; endoplasmic reticulum; glucose consumption; metformin; tumor metabolism

DOI:  https://doi.org/10.3390/biom11081231
Biofactors. 2021 Aug 28.

Protein networks linking Warburg and reverse Warburg effects to cancer cell metabolism.

Dina Johar, Ahmed O Elmehrath, Rania M Khalil, Mostafa H Elberry, Samy Zaky, Samy A Shalabi, Larry H Bernstein.

  It was 80 years after the Otto Warburg discovery of aerobic glycolysis, a major hallmark in the understanding of cancer. The Warburg effect is the preference of cancer cell for glycolysis that produces lactate even when sufficient oxygen is provided. "reverse Warburg effect" refers to the interstitial tissue communications with adjacent epithelium, that in the process of carcinogenesis, is needed to be explored. Among these cell-cell communications, the contact between epithelial cells; between epithelial cells and matrix; and between fibroblasts and inflammatory cells in the underlying matrix. Cancer involves dysregulation of Warburg and reverse Warburg cellular metabolic pathways. How these gene and protein-based regulatory mechanisms have functioned has been the basis for this review. The importance of the Warburg in oxidative phosphorylation suppression, with increased glycolysis in cancer growth and proliferation is emphasized. Studies that are directed at pathways that would be expected to shift cell metabolism to an increased oxidation and to a decrease in glycolysis are emphasized. Key enzymes required for oxidative phosphorylation, and affect the inhibition of fatty acid metabolism and glutamine dependence are conferred. The findings are of special interest to cancer pharmacotherapy. Studies described in this review are concerned with the effects of therapeutic modalities that are intimately related to the Warburg effect. These interactions described may be helpful as adjuvant therapy in controlling the process of proliferation and metastasis.

Keywords:  Warburg; aerobic; anaerobic; cancer; glycolysis; metastasis; proliferation; tumorigenesis

DOI:  https://doi.org/10.1002/biof.1768
Biomolecules. 2021 Jul 31. pii: 1130. [Epub ahead of print]11(8):

Understanding the Therapeutic Potential of Ascorbic Acid in the Battle to Overcome Cancer.

Jurnal Reang, Prabodh Chander Sharma, Vijay Kumar Thakur, Jaseela Majeed.

  Cancer, a fatal disease, is also one of the main causes of death worldwide. Despite various developments to prevent and treat cancer, the side effects of anticancer drugs remain a major concern. Ascorbic acid is an essential vitamin required by our bodies for normal physiological function and also has antioxidant and anticancer activity. Although the body cannot synthesize ascorbic acid, it is abundant in nature through foods and other natural sources and also exists as a nutritional food supplement. In anticancer drug development, ascorbic acid has played an important role by inhibiting the development of cancer through various mechanisms, including scavenging reactive oxygen species (ROS), selectively producing ROS and encouraging their cytotoxicity against tumour cells, preventing glucose metabolism, serving as an epigenetic regulator, and regulating the expression of HIF in tumour cells. Several ascorbic acid analogues have been produced to date for their anticancer and antioxidant activity. The current review summarizes the mechanisms behind ascorbic acid's antitumor activity, presents a compilation of its derivatives and their biological activity as anticancer agents, and discusses delivery systems such as liposomes, nanoparticles against cancer, and patents on ascorbic acid as anticancer agents.

Keywords:  HIF; anticancer; antioxidant; ascorbic acid; cancer; epigenetic regulator; pro-oxidant

DOI:  https://doi.org/10.3390/biom11081130
Biomedicines. 2021 Jul 23. pii: 876. [Epub ahead of print]9(8):

TNBC: Potential Targeting of Multiple Receptors for a Therapeutic Breakthrough, Nanomedicine, and Immunotherapy.

Desh Deepak Singh, Dharmendra Kumar Yadav.

  Triple-negative breast cancer (TNBC) is a heterogeneous, recurring cancer associated with a high rate of metastasis, poor prognosis, and lack of therapeutic targets. Although target-based therapeutic options are approved for other cancers, only limited therapeutic options are available for TNBC. Cell signaling and receptor-specific targets are reportedly effective in patients with TNBC under specific clinical conditions. However, most of these cancers are unresponsive, and there is a requirement for more effective treatment modalities. Further, there is a lack of effective biomarkers that can distinguish TNBC from other BC subtypes. ER, PR, and HER2 help identify TNBC and are widely used to identify patients who are most likely to respond to diverse therapeutic strategies. In this review, we discuss the possible treatment options for TNBC based on its inherent subtype receptors and pathways, such as p53 signaling, AKT signaling, cell cycle regulation, DNA damage, and programmed cell death, which play essential roles at multiple stages of TNBC development. We focus on poly-ADP ribose polymerase 1, androgen receptor, vascular endothelial growth factor receptor, and epidermal growth factor receptor as well as the application of nanomedicine and immunotherapy in TNBC and discuss their potential applications in drug development for TNBC.

Keywords:  clinical trial; signaling pathway; therapeutic target; triple-negative breast cancer

DOI:  https://doi.org/10.3390/biomedicines9080876
Biochim Biophys Acta Rev Cancer. 2021 Aug 21. pii: S0304-419X(21)00116-5. [Epub ahead of print] 188618

The role of 5-HT metabolism in cancer.

Di Ye, Huanji Xu, Qiulin Tang, Hongwei Xia, Chenliang Zhang, Feng Bi.

  Serotonin (5-hydroxytryptamine, 5-HT) metabolism has long been linked to tumorigenesis and tumor progression. Numerous studies have shown the functions of 5-HT and its metabolites in the regulation of tumor biological processes like cell proliferation, invasion, metastasis, tumor angiogenesis and immunomodulatory through multi-step complex mechanisms. Reprogramming of 5-HT metabolism has been revealed in various tumors paving way for development of drugs that target enzymes, metabolites or receptors involved in 5-HT metabolic pathway. However, information on the role of 5-HT metabolism in cancer is scanty. This review briefly describes the main metabolic routes of 5-HT, the role of 5-HT metabolism in cancer and systematically summarizes the most recent advances in 5-HT metabolism-targeted cancer therapy.

Keywords:  Cancer therapy; Metabolism; Serotonin

DOI:  https://doi.org/10.1016/j.bbcan.2021.188618
Biomolecules. 2021 Aug 18. pii: 1232. [Epub ahead of print]11(8):

Pathophysiological Roles of Histamine Receptors in Cancer Progression: Implications and Perspectives as Potential Molecular Targets.

Phuong Linh Nguyen, Jungsook Cho.

  High levels of histamine and histamine receptors (HRs), including H1R~H4R, are found in many different types of tumor cells and cells in the tumor microenvironment, suggesting their involvement in tumor progression. This review summarizes the latest evidence demonstrating the pathophysiological roles of histamine and its cognate receptors in cancer biology. We also discuss the novel therapeutic approaches of selective HR ligands and their potential prognostic values in cancer treatment. Briefly, histamine is highly implicated in cancer development, growth, and metastasis through interactions with distinct HRs. It also regulates the infiltration of immune cells into the tumor sites, exerting an immunomodulatory function. Moreover, the effects of various HR ligands, including H1R antagonists, H2R antagonists, and H4R agonists, on tumor progression in many different cancer types are described. Interestingly, the expression levels of HR subtypes may serve as prognostic biomarkers in several cancers. Taken together, HRs are promising targets for cancer treatment, and HR ligands may offer novel therapeutic potential, alone or in combination with conventional therapy. However, due to the complexity of the pathophysiological roles of histamine and HRs in cancer biology, further studies are warranted before HR ligands can be introduced into clinical settings.

Keywords:  cancer progression; histamine; histamine receptor ligands; histamine receptors; molecular target; prognostic biomarkers; tumor microenvironment

DOI:  https://doi.org/10.3390/biom11081232
Epigenomics. 2021 Aug 27.

Essential amino acid metabolism-related molecular classification in triple-negative breast cancer.

Yajie Zhao, Chunrui Pu, Dechuang Jiao, Jiujun Zhu, Xuhui Guo, Zhenzhen Liu.

  Aim: To develop an approach to characterize and classify triple-negative breast cancer (TNBC) tumors based upon their essential amino acid (EAA) metabolic activity. Methods: We performed bioinformatic analyses of genomic, transcriptomic and clinical data in an integrated cohort of 740 TNBC patients from public databases. Results: Based on EAA metabolism-related gene expression patterns, two TNBC subtypes were identified with distinct prognoses and genomic alterations. Patients exhibiting an upregulated EAA metabolism phenotype were more prone to chemoresistance but also expressed higher levels of immune checkpoint genes and may be better candidates for immune checkpoint inhibitor therapy. Conclusion: Metabolic classification based upon EAA profiles offers a novel biological insight into previously established TNBC subtypes and advances current understanding of TNBC's metabolic heterogeneity.

Keywords:  PD-1; TNBC; bioinformatics; chemoresistance; classification; epigenomics; essential amino acid; immunotherapy; metabolic heterogeneity; prognosis

DOI:  https://doi.org/10.2217/epi-2021-0210
Front Nutr. 2021 ;8 703392

A Root in Synapsis and the Other One in the Gut Microbiome-Brain Axis: Are the Two Poles of Ketogenic Diet Enough to Challenge Glioblastoma?

Liliana Montella, Federica Sarno, Lucia Altucci, Valentina Cioffi, Luigi Sigona, Salvatore Di Colandrea, Stefano De Simone, Alfredo Marinelli, Bianca Arianna Facchini, Ferdinando De Vita, Massimiliano Berretta, Raffaele de Falco, Gaetano Facchini.

  Glioblastoma is the most frequent and aggressive brain cancer in adults. While precision medicine in oncology has produced remarkable progress in several malignancies, treatment of glioblastoma has still limited available options and a dismal prognosis. After first-line treatment with surgery followed by radiochemotherapy based on the 2005 STUPP trial, no significant therapeutic advancements have been registered. While waiting that genomic characterization moves from a prognostic/predictive value into therapeutic applications, practical and easy-to-use approaches are eagerly awaited. Medical reports on the role of the ketogenic diet in adult neurological disorders and in glioblastoma suggest that nutritional interventions may condition outcomes and be associated with standard therapies. The acceptable macronutrient distribution of daily calories in a regular diet are 45-65% of daily calories from carbohydrates, 20-35% from fats, and 10-35% from protein. Basically, the ketogenic diet follows an approach based on low carbohydrates/high fat intake. In carbohydrates starvation, body energy derives from fat storage which is used to produce ketones and act as glucose surrogates. The ketogenic diet has several effects: metabolic interference with glucose and insulin and IGF-1 pathways, influence on neurotransmission, reduction of oxidative stress and inflammation, direct effect on gene expression through epigenetic mechanisms. Apart from these central effects working at the synapsis level, recent evidence also suggests a role for microbiome and gut-brain axis induced by a ketogenic diet. This review focuses on rationales supporting the ketogenic diet and clinical studies will be reported, looking at future possible perspectives.

Keywords:  glioblastoma; gut-brain axis; ketogenic diet; microbiota; warburg effect

DOI:  https://doi.org/10.3389/fnut.2021.703392
Front Genet. 2021 ;12 672904

Ferroptosis-Related Genes in Lung Adenocarcinoma: Prognostic Signature and Immune, Drug Resistance, Mutation Analysis.

Ziyuan Ren, Minghui Hu, Zhonglin Wang, Junpeng Ge, Xiaoyan Zhou, Guoming Zhang, Hongying Zheng.

  It is reported that ferroptosis has close relation with tumorigenesis and drug resistance. However, the clinical significance of ferroptosis in lung adenocarcinoma (LUAD) remains elusive, and the potential targets for ferroptosis-based treatment are limited. In this study, we constructed a 15-gene prognostic signature predicting overall survival based on ferroptosis-related genes (ferroptosis driver genes VDAC2, GLS2, FLT3, TLR4, PHKG2, phosphogluconate dehydrogenase (PGD), PANX1, KRAS, PEBP1, ALOX15, and ALOX12B, and suppressor genes ACSL3, CISD1, FANCD2, and SLC3A2) in The Cancer Genome Atlas (TCGA)-LUAD cohort. The signature's predictive ability was validated in the GSE68465 and GSE72094 cohorts by survival analysis and independent prognostic analysis with clinical features. Nomograms were provided for clinical reference. Functional analysis revealed that ferroptosis was closely related to cell cycle, cell metabolism, and immune pathways. Pan-cancer analysis comprehensively analyzed these 15 genes in 33 cancer types, indicating that the heterogeneity of 15 genes was evident across different cancer types. Besides, these genes were critical regulators modulating drug resistance, tumor microenvironment infiltration, and cancer stemness. Then, we screened 10 genes (TLR4, PHKG2, PEBP1, GLS2, FLT3, ALOX15, ACSL3, CISD1, FANCD2, and SLC3A2) as potential targets for further research because their biological functions in ferroptosis were consistent with their prognostic significance. Somatic mutation and copy number variation analysis revealed that the alteration rates of KRAS, PGD, and ALOX15 were more than 1% and significantly associated with overall survival in LUAD. Moreover, the expression of KRAS and PGD was positively related to tumor mutation burden, indicating that KRAS and PGD could serve as novel biomarkers for predicting immunotherapy response rate. Our study identified and validated a ferroptosis-related gene signature for LUAD, provided a 10-gene set for future research, and screened KRAS and PGD as potential novel immunotherapy biomarkers.

Keywords:  copy number variation; drug resistance; ferroptosis; lung adenocarcinoma; prognosis; somatic mutation; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fgene.2021.672904
Biomolecules. 2021 Aug 09. pii: 1176. [Epub ahead of print]11(8):

Role of Phytonutrients in Nutrigenetics and Nutrigenomics Perspective in Curing Breast Cancer.

Tanima Bhattacharya, Soumam Dutta, Rokeya Akter, Md Habibur Rahman, Chenmala Karthika, Hechanur Puttappa Nagaswarupa, Hanabe Chowdappa Ananda Murthy, Ovidiu Fratila, Roxana Brata, Simona Bungau.

  Breast cancer (BC) is one of the most common type of cancer and an important contributor to female mortality. Several genes and epigenetic modifications are involved in the development and progression of BC. Research in phytochemistry, nutrigenomics, and nutrigenetics has provided strong evidence that certain phytonutrients are able to modulate gene expression at transcriptional and post-transcriptional levels. Such phytonutrients may also be beneficial to prevent and treat BC. In this review, we will focus on the nutrigenomic effects of various phytochemicals including polyphenols, phytosterols, terpenoids, alkaloids, and other compounds from different sources. Overall, these phytonutrients are found to inhibit BC cell proliferation, differentiation, invasion, metastasis, angiogenesis, and induce apoptotic cell death by targeting various molecular pathways. They also alter epigenetic mechanisms and enhance the chemosensitivity and radiosensitivity of cancer cells. Such phytochemicals may be used for the effective management of BC patients in the clinical setting in the future. The present article aims to summarize the specific molecular pathways involved in the genetic effects of phytochemicals in BC.

Keywords:  breast cancer; chemosensitizer; gene expression; natural compounds; nutrigenomic; phytonutrients; polyphenols

DOI:  https://doi.org/10.3390/biom11081176
Pharmaceuticals (Basel). 2021 Jul 29. pii: 740. [Epub ahead of print]14(8):

Epithelial to Mesenchymal Transition in Patients with Pancreatic Ductal Adenocarcinoma: State-of-the-Art and Therapeutic Opportunities.

Julie Dardare, Andréa Witz, Jean-Louis Merlin, Agathe Bochnakian, Paul Toussaint, Pauline Gilson, Alexandre Harlé.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the malignancies with the worst prognosis despite a decade of efforts. Up to eighty percent of patients are managed at late stages with metastatic disease, in part due to a lack of diagnosis. The effectiveness of PDAC therapies is challenged by the early and widespread metastasis. Epithelial to mesenchymal transition (EMT) is a major driver of cancer progression and metastasis. This process allows cancer cells to gain invasive properties by switching their phenotype from epithelial to mesenchymal. The importance of EMT has been largely described in PDAC, and its importance is notably highlighted by the two major subtypes found in PDAC: the classical epithelial and the quasi-mesenchymal subtypes. Quasi-mesenchymal subtypes have been associated with a poorer prognosis. EMT has also been associated with resistance to treatments such as chemotherapy and immunotherapy. EMT is associated with several key molecular markers both epithelial and mesenchymal. Those markers might be helpful as a biomarker in PDAC diagnosis. EMT might becoming a key new target of interest for the treatment PDAC. In this review, we describe the role of EMT in PDAC, its contribution in diagnosis, in the orientation and treatment follow-up. We also discuss the putative role of EMT as a new therapeutic target in the management of PDAC.

Keywords:  EMT; PDAC; biomarker; metastasis

DOI:  https://doi.org/10.3390/ph14080740
Cancers (Basel). 2021 Aug 20. pii: 4184. [Epub ahead of print]13(16):

Glucose Transporters as a Target for Anticancer Therapy.

Monika Pliszka, Leszek Szablewski.

  Tumor growth causes cancer cells to become hypoxic. A hypoxic condition is a hallmark of cancer. Metabolism of cancer cells differs from metabolism of normal cells. Cancer cells prefer the process of glycolysis as a source of ATP. Process of glycolysis generates only two molecules of ATP per one molecule of glucose, whereas the complete oxidative breakdown of one molecule of glucose yields 36 molecules of ATP. Therefore, cancer cells need more molecules of glucose in comparison with normal cells. Increased uptake of glucose by these cells is due to overexpression of glucose transporters, especially GLUT1 and GLUT3, that are hypoxia responsive, as well as other glucose transport proteins. Increased expression of these carrier proteins may be used in anticancer therapy. This phenomenon is used in diagnostic techniques such as FDG-PET. It is also suggested, and there are observations, that therapeutic inhibition of glucose transporters may be a method in treatment of cancer patients. On the other hand, there are described cases, in which upregulation of glucose transporters, as, for example, NIS, which is used in radioiodine therapy, can help patients with cancer. The aim of this review is the presentation of possibilities, and how glucose transporters can be used in anticancer therapy.

Keywords:  GLUT proteins; cancers therapy; sodium-dependent glucose cotransporters

DOI:  https://doi.org/10.3390/cancers13164184
J Cell Sci. 2021 Jan 15. pii: jcs247056. [Epub ahead of print]134(2):

The pleiotropic functions of autophagy in metastasis.

Timothy Marsh, Bhairavi Tolani, Jayanta Debnath.

  Autophagy is deregulated in many cancers and represents an attractive target for therapeutic intervention. However, the precise contributions of autophagy to metastatic progression, the principle cause of cancer-related mortality, is only now being uncovered. While autophagy promotes primary tumor growth, metabolic adaptation and resistance to therapy, recent studies have unexpectedly revealed that autophagy suppresses the proliferative outgrowth of disseminated tumor cells into overt and lethal macrometastases. These studies suggest autophagy plays unexpected and complex roles in the initiation and progression of metastases, which will undoubtedly impact therapeutic approaches for cancer treatment. Here, we discuss the intricacies of autophagy in metastatic progression, highlighting and integrating the pleiotropic roles of autophagy on diverse cell biological processes involved in metastasis.

Keywords:  Autophagy; Cancer; Metastasis; Selective Autophagy

DOI:  https://doi.org/10.1242/jcs.247056
Curr Drug Targets. 2021 Aug 24.

A comprehensive review on Chrysin: Emphasis on Molecular targets, Pharmacological actions and Bio-pharmaceutical aspects.

Anuj Garg, Shashank Chaturvedi.

  Chrysin (a flavonoid) showed various promising pharmacological activities viz. anti-cancer, anti-diabetic, immune-modulation, antidepressant, and anti-asthmatic. Additionally, it exhibited potential protective effects against various toxins on different organs like the liver, brain, kidney, and heart. A multitude of studies has been conducted to explore the possible targets for its possible mechanism of action. However, its therapeutic applications have been limited due to its poor oral bioavailability. The major reason for its poor bioavailability is its extensive first-pass metabolism. A critical review of the pharmacological properties of Chrysin and its associated molecular targets has not been discussed as yet comprehensively. Therefore, the emphasis of the present work is to provide an in-depth understanding of molecular targets accountable for the pharmacological actions of Chrysin. Moreover, a schematic diagram was made the first time for representing the comprehensive pharmacokinetic properties of Chrysin which helps to understand the biopharmaceutical aspect for its successful delivery. An in-depth understanding of the biopharmaceutical properties of Chrysin will help in adopting a suitable formulation approach to overcome poor oral bioavailability. Additionally, it facilitates to study of the possible pharmacokinetic interactions of Chrysin with other drugs. Hence, we found that Chrysin is a miraculous natural agent with myriad therapeutic properties and its benefit can be exploited with an in-depth understanding of molecular targets, pharmacological actions, and biopharmaceutical attributes.

Keywords:  Chrysin; anti-diabetic; anticancer; antidepressant; antiviral; chemopreventive; pharmacokinetic; protective effect

DOI:  https://doi.org/10.2174/1389450122666210824141044
Int J Mol Sci. 2021 Aug 16. pii: 8812. [Epub ahead of print]22(16):

The Involvement of Natural Polyphenols in the Chemoprevention of Cervical Cancer.

Georgiana Drețcanu, Cristian I Iuhas, Zorița Diaconeasa.

  From all types of cancer, cervical cancer manages to be in top four most frequent types, with a 6.5% rate of occurrence. The infectious vector that induces the disease, the high-risk Human papillomavirus (HPV), which is a sexually transmitted virus, is capable of transforming the host cell by modulating some of the principal signaling pathways responsible for cell cycle arrest, proliferation, and survival. Fortunately, like other cancer types, cervical cancer can be treated by chirurgical interventions or chemoradiotherapy, but these methods are not exactly the lucky clover of modern medicine because of the adverse effects they have. That is the reason why in the last years the emphasis has been on alternative medicine, more specifically on phytochemicals, as a substantial number of studies showed that diet contributes to cancer prevention and treatment. All these studies are trying to find new chemopreventive agents with less toxicity but high effectiveness both in vitro and in vivo. The aim of this review is to evaluate the literature in order to underline the advantages and disadvantages of polyphenols, a class of dietary compounds, as chemopreventive and chemotherapeutic agents. This review also aims to present polyphenols from different perspectives, starting with mechanisms of action and ending with their toxicity. The bigger picture illustrates that polyphenols have great potential in cervical cancer prevention, with strong effects on gene modulation.

Keywords:  HPV; apoptosis; cervical cancer; phytochemicals; polyphenols; toxicity

DOI:  https://doi.org/10.3390/ijms22168812
Front Cell Dev Biol. 2021 ;9 691161

Identification of Novel Metabolism-Associated Subtypes for Pancreatic Cancer to Establish an Eighteen-Gene Risk Prediction Model.

Yang Gao, Enchong Zhang, Xiang Fei, Lingming Kong, Peng Liu, Xiaodong Tan.

  Pancreatic cancer (PanC) is an intractable malignancy with a high mortality. Metabolic processes contribute to cancer progression and therapeutic responses, and histopathological subtypes are insufficient for determining prognosis and treatment strategies. In this study, PanC subtypes based on metabolism-related genes were identified and further utilized to construct a prognostic model. Using a cohort of 171 patients from The Cancer Genome Atlas (TCGA) database, transcriptome data, simple nucleotide variants (SNV), and clinical information were analyzed. We divided patients with PanC into metabolic gene-enriched and metabolic gene-desert subtypes. The metabolic gene-enriched subgroup is a high-risk subtype with worse outcomes and a higher frequency of SNVs, especially in KRAS. After further characterizing the subtypes, we constructed a risk score algorithm involving multiple genes (i.e., NEU2, GMPS, PRIM2, PNPT1, LDHA, INPP4B, DPYD, PYGL, CA12, DHRS9, SULT1E1, ENPP2, PDE1C, TPH1, CHST12, POLR3GL, DNMT3A, and PGS1). We verified the reproducibility and reliability of the risk score using three validation cohorts (i.e., independent datasets from TCGA, Gene Expression Omnibus, and Ensemble databases). Finally, drug prediction was completed using a ridge regression model, yielding nine candidate drugs for high-risk patients. These findings support the classification of PanC into two metabolic subtypes and further suggest that the metabolic gene-enriched subgroup is associated with worse outcomes. The newly established risk model for prognosis and therapeutic responses may improve outcomes in patients with PanC.

Keywords:  metabolic genes; pancreatic cancer; risk model; subtype; transcriptome

DOI:  https://doi.org/10.3389/fcell.2021.691161
Biomolecules. 2021 Aug 09. pii: 1177. [Epub ahead of print]11(8):

The Effect of Oxygen and Micronutrient Composition of Cell Growth Media on Cancer Cell Bioenergetics and Mitochondrial Networks.

Fereshteh Moradi, Christopher Moffatt, Jeffrey A Stuart.

  Cancer cell culture is routinely performed under superphysiologic O2 levels and in media such as Dulbecco's Modified Eagle Medium (DMEM) with nutrient composition dissimilar to mammalian extracellular fluid. Recently developed cell culture media (e.g., Plasmax, Human Plasma-Like Medium (HPLM)), which are modeled on the metabolite composition of human blood plasma, have been shown to shift key cellular activities in several cancer cell lines. Similar effects have been reported with respect to O2 levels in cell culture. Given these observations, we investigated how media composition and O2 levels affect cellular energy metabolism and mitochondria network structure in MCF7, SaOS2, LNCaP, and Huh7 cells. Cells were cultured in physiologic (5%) or standard (18%) O2 levels, and in physiologic (Plasmax) or standard cell culture media (DMEM). We show that both O2 levels and media composition significantly affect mitochondrial abundance and network structure, concomitantly with changes in cellular bioenergetics. Extracellular acidification rate (ECAR), a proxy for glycolytic activity, was generally higher in cells cultured in DMEM while oxygen consumption rates (OCR) were lower. This effect of media on energy metabolism is an important consideration for the study of cancer drugs that target aspects of energy metabolism, including lactate dehydrogenase activity.

Keywords:  cell culture; glycolysis; metabolism; mitochondria; mitochondrial networks; oxidative phosphorylation

DOI:  https://doi.org/10.3390/biom11081177
Pharmacol Res. 2021 Aug 24. pii: S1043-6618(21)00418-7. [Epub ahead of print] 105834

Metabolic Enzymes Function as Epigenetic Modulators: A Trojan Horse for Chromatin Regulation and Gene Expression.

Xiaoyu Liao, Yifan Guo, Yumin He, Yanxuan Xiao, Jingyi Li, Rui Liu.

  Epigenetic modification is a fundamental biological process in living organisms, which has significant impact on health and behavior. Metabolism refers to a set of life-sustaining chemical reactions, including the uptake of nutrients, the subsequent conversion of nutrients into energy or building blocks for organism growth, and finally the clearance of redundant or toxic substances. It is well established that epigenetic modifications govern the metabolic profile of a cell by modulating the expression of metabolic enzymes. Strikingly, almost all the epigenetic modifications require substrates produced by cellular metabolism, and a large proportion of metabolic enzymes can transfer into nucleus to locally produce substrates for epigenetic modification, thereby providing an alternative link between metabolism, epigenetic modification and gene expression. Here, we summarize the recent literature pertinent to metabolic enzymes functioning as epigenetic modulators in the regulation of chromatin architecture and gene expression.

Keywords:  RNA modification; epigenetic modification; gene expression; metabolic enzyme; metabolites

DOI:  https://doi.org/10.1016/j.phrs.2021.105834
Prog Biophys Mol Biol. 2021 Aug 19. pii: S0079-6107(21)00098-5. [Epub ahead of print]

Metabolite Biomarkers of Response (BoRs): Towards a fingerprint for the evolution of metastatic breast cancer.

Josephine Wolf, Chen Dong, Elizabeth M O'Day.

  Breast cancer is the most common cancer in women worldwide and despite improved treatment strategies, it persists as the second leading cause of death of women globally. Overall prognosis drops drastically once the cancer has metastasized, which is also associated with resistance to therapy. The evolution from a localized breast cancer to metastatic disease is complex and multifactorial. Metabolic reprogramming is a pre-requisite for this transition. In this graphical review, we provide an overview of altered metabolic pathways observed in metastatic breast cancer (mBC) and detail how metabolite biomarkers could serve as a novel class of precision medicine tools to improve the diagnosis, monitoring, and treatment of mBC.

Keywords:  Biomarkers; Cancer; Metabolism; Precision medicine; Resistance

DOI:  https://doi.org/10.1016/j.pbiomolbio.2021.08.005
Cell Signal. 2021 Aug 23. pii: S0898-6568(21)00211-4. [Epub ahead of print] 110122

An overview on the biological activity and anti-cancer mechanism of lovastatin.

Liguo Xie, Guodong Zhu, Junjie Shang, Xuemei Chen, Chunting Zhang, Xiuling Ji, Qi Zhang, Yunlin Wei.

  Lovastatin, a secondary metabolite isolated from fungi, is often used as a representative drug to reduce blood lipid concentration and treat hypercholesterolemia. Its structure is similar to that of HMG-CoA. Lovastatin inhibits the binding of the substrate to HMG-CoA reductase, and strongly competes with HMG-CoA reductase (HMGR), thereby exerting a hypolipidemic effect. Further, its safety has been confirmed in vivo and in vitro. Lovastatin also has anti-inflammatory, anti-cancer, and neuroprotective effects. Therefore, the biological activity of lovastatin, especially its anti-cancer effect, has garnered research attention. Several in vitro studies have confirmed that lovastatin has a significant inhibitory effect on cancer cell viability in a variety of cancers (such as breast, liver, cervical, lung, and colon cancer). At the same time, lovastatin can also increase the sensitivity of some types of cancer cells to chemotherapeutic drugs and strengthen their therapeutic effect. Lovastatin inhibits cell proliferation and regulates cancer cell signaling pathways, thereby inducing apoptosis and cell cycle arrest. This article reviews the structure, biosynthetic pathways, and applications of lovastatin, focusing on the anti-cancer effects and mechanisms of action.

Keywords:  Anticancer; Bioactivity; Biosynthesis; Lovastatin; Mechanism

DOI:  https://doi.org/10.1016/j.cellsig.2021.110122