bims-kracam 2021-08-08 papers

on K-Ras in cancer metabolism

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

NUPR1: A Critical Regulator of the Antioxidant System.
Primary Aldosteronism: Metabolic Reprogramming and the Pathogenesis of Aldosterone-Producing Adenomas.
Tumor pyruvate kinase M2 modulators: a comprehensive account of activators and inhibitors as anticancer agents.
Potential Therapies Targeting Metabolic Pathways in Cancer Stem Cells.
Metabolic control of cancer progression as novel targets for therapy.
The transcription factor BACH1 at the crossroads of cancer biology: From epithelial-mesenchymal transition to ferroptosis.
Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer.
Sulforaphane as a potential remedy against cancer: Comprehensive mechanistic review.
Flavonoids and PI3K/Akt/mTOR signaling cascade: A potential crosstalk in anticancer treatment.
Ending on a sour note: Lipids orchestrate ferroptosis in cancer.
Matrix Stiffness Modulates Metabolic Interaction between Human Stromal and Breast Cancer Cells to Stimulate Epithelial Motility.
Metabostemness in cancer: Linking metaboloepigenetics and mitophagy in remodeling cancer stem cells.
Potential of Olive oil and its phenolic compounds as therapeutic intervention against colorectal cancer: A comprehensive review.
Metabolic reprograming confers tamoxifen resistance in breast cancer.
IDH Mutations in Glioma: Double-Edged Sword in Clinical Applications?
Reductive stress in cancer.
Ketogenesis impact on liver metabolism revealed by proteomics of lysine β-hydroxybutyrylation.
Inhibitors Targeting CDK9 Show High Efficacy against Osimertinib and AMG510 Resistant Lung Adenocarcinoma Cells.
Cytotoxic activity of KRAS inhibitors in combination with chemotherapeutics.
ASN007 is a selective ERK1/2 inhibitor with preferential activity against RAS-and RAF-mutant tumors.
Hypoxia promotes breast cancer cell growth by activating a glycogen metabolic program.
The Green Anti-Cancer Weapon. The Role of Natural Compounds in Bladder Cancer Treatment.
Efficacy of rigosertib, a small molecular RAS signaling disrupter for the treatment of KRAS-mutant colorectal cancer.
Physciosporin suppresses mitochondrial respiration, aerobic glycolysis, and tumorigenesis in breast cancer.
The Importance of Being PI3K in the RAS Signaling Network.

Cancers (Basel). 2021 Jul 22. pii: 3670. [Epub ahead of print]13(15):

NUPR1: A Critical Regulator of the Antioxidant System.

Can Huang, Patricia Santofimia-Castaño, Juan Iovanna.

  Nuclear protein 1 (NUPR1) is a small intrinsically disordered protein (IDP) activated in response to various types of cellular stress, including endoplasmic reticulum (ER) stress and oxidative stress. Reactive oxygen species (ROS) are mainly produced during mitochondrial oxidative metabolism, and directly impact redox homeostasis and oxidative stress. Ferroptosis is a ROS-dependent programmed cell death driven by an iron-mediated redox reaction. Substantial evidence supports a maintenance role of the stress-inducible protein NUPR1 on cancer cell metabolism that confers chemotherapeutic resistance by upregulating mitochondrial function-associated genes and various antioxidant genes in cancer cells. NUPR1, identified as an antagonist of ferroptosis, plays an important role in redox reactions. This review summarizes the current knowledge on the mechanism behind the observed impact of NUPR1 on mitochondrial function, energy metabolism, iron metabolism, and the antioxidant system. The therapeutic potential of genetic or pharmacological inhibition of NUPR1 in cancer is also discussed. Understanding the role of NUPR1 in the antioxidant system and the mechanisms behind its regulation of ferroptosis may promote the development of more efficacious strategies for cancer therapy.

Keywords:  NUPR1; ROS; cell death; cell stress; ferroptosis

DOI:  https://doi.org/10.3390/cancers13153670
Cancers (Basel). 2021 Jul 23. pii: 3716. [Epub ahead of print]13(15):

Primary Aldosteronism: Metabolic Reprogramming and the Pathogenesis of Aldosterone-Producing Adenomas.

Siyuan Gong, Martina Tetti, Martin Reincke, Tracy Ann Williams.

  Aldosterone-producing adenomas (APAs) are characterized by aldosterone hypersecretion and deregulated adrenocortical cell growth. Increased energy consumption required to maintain cellular tumorigenic properties triggers metabolic alterations that shape the tumor microenvironment to acquire necessary nutrients, yet our knowledge of this adaptation in APAs is limited. Here, we investigated adrenocortical cell-intrinsic metabolism and the tumor immune microenvironment of APAs and their potential roles in mediating aldosterone production and growth of adrenocortical cells. Using multiple advanced bioinformatics methods, we analyzed gene expression datasets to generate distinct metabolic and immune cell profiles of APAs versus paired adjacent cortex. APAs displayed activation of lipid metabolism, especially fatty acid β-oxidation regulated by PPARα, and glycolysis. We identified an immunosuppressive microenvironment in APAs, with reduced infiltration of CD45+ immune cells compared with adjacent cortex, validated by CD45 immunohistochemistry (3.45-fold, p < 0.001). APAs also displayed an association of lipid metabolism with ferroptosis and upregulation of antioxidant systems. In conclusion, APAs exhibit metabolic reprogramming towards fatty acid β-oxidation and glycolysis. Increased lipid metabolism via PPARα may serve as a key mechanism to modulate lipid peroxidation, a hallmark of regulated cell death by ferroptosis. These findings highlight survival advantages for APA tumor cells with metabolic reprogramming properties.

Keywords:  PPARα; adaptive metabolism; adrenal gland; conn adenoma; fatty acid metabolism; ferroptosis; hyperaldosteronism; metabolic reprogramming; tumor microenvironment; β-oxidation

DOI:  https://doi.org/10.3390/cancers13153716
RSC Med Chem. 2021 Jul 21. 12(7): 1121-1141

Tumor pyruvate kinase M2 modulators: a comprehensive account of activators and inhibitors as anticancer agents.

Bhagyashri Rathod, Shivam Chak, Sagarkumar Patel, Amit Shard.

Pyruvate kinase M2 (PKM2) catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate. It plays a central role in the metabolic reprogramming of cancer cells and is expressed in most human tumors. It is essential in indiscriminate proliferation, survival, and tackling apoptosis in cancer cells. This positions PKM2 as a hot target in cancer therapy. Despite its well-known structure and several reported modulators targeting PKM2 as activators or inhibitors, a comprehensive review focusing on such modulators is lacking. Herein we summarize modulators of PKM2, the assays used to detect their potential, the preferable tense (T) and relaxed (R) states in which the enzyme resides, lacunae in existing modulators, and several strategies that may lead to effective anticancer drug development targeting PKM2.

DOI: https://doi.org/10.1039/d1md00045d
Cells. 2021 Jul 13. pii: 1772. [Epub ahead of print]10(7):

Potential Therapies Targeting Metabolic Pathways in Cancer Stem Cells.

Yao-An Shen, Chang-Cyuan Chen, Bo-Jung Chen, Yu-Ting Wu, Jiun-Ru Juan, Liang-Yun Chen, Yueh-Chun Teng, Yau-Huei Wei.

  Cancer stem cells (CSCs) are heterogeneous cells with stem cell-like properties that are responsible for therapeutic resistance, recurrence, and metastasis, and are the major cause for cancer treatment failure. Since CSCs have distinct metabolic characteristics that plays an important role in cancer development and progression, targeting metabolic pathways of CSCs appears to be a promising therapeutic approach for cancer treatment. Here we classify and discuss the unique metabolisms that CSCs rely on for energy production and survival, including mitochondrial respiration, glycolysis, glutaminolysis, and fatty acid metabolism. Because of metabolic plasticity, CSCs can switch between these metabolisms to acquire energy for tumor progression in different microenvironments compare to the rest of tumor bulk. Thus, we highlight the specific conditions and factors that promote or suppress CSCs properties to portray distinct metabolic phenotypes that attribute to CSCs in common cancers. Identification and characterization of the features in these metabolisms can offer new anticancer opportunities and improve the prognosis of cancer. However, the therapeutic window of metabolic inhibitors used alone or in combination may be rather narrow due to cytotoxicity to normal cells. In this review, we present current findings of potential targets in these four metabolic pathways for the development of more effective and alternative strategies to eradicate CSCs and treat cancer more effectively in the future.

Keywords:  cancer stem cell; fatty acid metabolism; glutamninolysis; glycolysis; metabolic pathway; metabolic plasticity; mitochondrial respiration

DOI:  https://doi.org/10.3390/cells10071772
Adv Cancer Res. 2021 ;pii: S0065-230X(21)00049-X. [Epub ahead of print]152 103-177

Metabolic control of cancer progression as novel targets for therapy.

Sarmistha Talukdar, Luni Emdad, Rajan Gogna, Swadesh K Das, Paul B Fisher.

  Metabolism is an important part of tumorigenesis as well as progression. The various cancer metabolism pathways, such as glucose metabolism and glutamine metabolism, directly regulate the development and progression of cancer. The pathways by which the cancer cells rewire their metabolism according to their needs, surrounding environment and host tissue conditions are an important area of study. The regulation of these metabolic pathways is determined by various oncogenes, tumor suppressor genes, as well as various constituent cells of the tumor microenvironment. Expanded studies on metabolism will help identify efficient biomarkers for diagnosis and strategies for therapeutic interventions and countering ways by which cancers may acquire resistance to therapy.

Keywords:  Cancer; Hypoxia; Metabolism; Therapy; Warburg effect

DOI:  https://doi.org/10.1016/bs.acr.2021.06.002
J Biol Chem. 2021 Jul 30. pii: S0021-9258(21)00834-6. [Epub ahead of print] 101032

The transcription factor BACH1 at the crossroads of cancer biology: From epithelial-mesenchymal transition to ferroptosis.

Kazuhiko Igarashi, Hironari Nishizawa, Yuriko Saiki, Mitsuyo Matsumoto.

  The progression of cancer involves not only the gradual evolution of cells by mutations in DNA but also alterations in the gene expression induced by those mutations and input from the surrounding microenvironment. Such alterations contribute to cancer cells' abilities to reprogram metabolic pathways and to undergo epithelial-to-mesenchymal transition (EMT), which facilitate the survival of cancer cells and their metastasis to other organs. Recently, BACH1 (BTB and CNC homology 1), a heme-regulated transcription factor that represses genes involved in iron- and heme-metabolism in normal cells, was shown to shape the metabolism and metastatic potential of cancer cells. The growing list of BACH1 target genes in cancer cells reveals that BACH1 promotes metastasis by regulating various sets of genes beyond iron metabolism. BACH1 represses the expression of genes that mediate cell-cell adhesion and oxidative phosphorylation, but activates the expression of genes required for glycolysis, cell motility, and matrix protein degradation. Furthermore, BACH1 represses FOXA1 gene encoding an activator of epithelial genes and activates SNAI2 encoding a repressor of epithelial genes, forming a feed-forward loop of EMT. By synthesizing these observations, we propose a "two-faced BACH1 model", which accounts for the dynamic switching between metastasis and stress-resistance along with cancer progression. We discuss here the possibility that BACH1-mediated promotion of cancer also brings increased sensitivity to iron-dependent cell death (ferroptosis) through crosstalk of BACH1 target genes, imposing programmed vulnerability upon cancer cells. We also discuss the future directions of this field, including the dynamics and plasticity of EMT.

Keywords:  BACH1; NRF2; cancer; epithelial-mesenchymal transition; ferroptosis; glycolysis; heme; iron; metastasis; transcription factor

DOI:  https://doi.org/10.1016/j.jbc.2021.101032
Cells. 2021 Jul 06. pii: 1715. [Epub ahead of print]10(7):

Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer.

Macus Hao-Ran Bao, Carmen Chak-Lui Wong.

  Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

Keywords:  ICIs; TKIs; drug resistance; hypoxia; liver cancer; metabolic reprogramming; metabolism

DOI:  https://doi.org/10.3390/cells10071715
J Food Biochem. 2021 Aug 05. e13886

Sulforaphane as a potential remedy against cancer: Comprehensive mechanistic review.

Iahtisham-Ul-Haq, Sipper Khan, Kanza Aziz Awan, Muhammad Jawad Iqbal.

  Sulforaphane belongs to the active class of isothiocyanates capable of delivering various biological benefits for health promotion and disease prevention. This compound is considered vital to curtail numerous metabolic disorders. Various studies have proven its beneficial effects against cancer prevention and its possible utilization as a therapeutic agent in cancer treatment. Understanding the mechanistic pathways and possible interactions at cellular and subcellular levels is key to design and develop cancer therapeutics for humans. In this respect, a number of mechanisms such as modulation of carcinogen metabolism & phase II enzymatic activities, cell cycle arrest, activation of Nrf2, cytotoxic, proapoptotic and apoptotic pathways have been reported to be involved in cancer prevention. This article provides sufficient information by critical analysis to understand the mechanisms involved in cancer prevention attributed to sulforaphane. Furthermore, various clinical studies have also been included for design and development of novel therapies for cancer prevention and cure. PRACTICAL APPLICATIONS: Diet and dietary components are potential tools to address various lifestyle-related disorders. Due to plenty of environmental and cellular toxicants, the chances of cancer prevalence are quite large which are worsen by adopting unhealthy lifestyles. Cancer can be treated with various therapies but those are acquiring side effects causing the patients to suffer the treatment regime. Nutraceuticals and functional foods provide safer options to prevent or delay the onset of cancer. In this regard, sulforaphane is a pivotal compound to be targeted as a potential agent for cancer treatment both in preventive and therapeutic regimes. This article provides sufficient evidence via discussing the underlying mechanisms of positive effects of sulforaphane to further the research for developing anticancer drugs that will help assuage this lethal morbidity.

Keywords:  anticancer; cruciferous vegetables; glucosinolates; isothiocyanate; sulforaphane

DOI:  https://doi.org/10.1111/jfbc.13886
Curr Med Chem. 2021 Aug 03.

Flavonoids and PI3K/Akt/mTOR signaling cascade: A potential crosstalk in anticancer treatment.

Badar Islam, Mohd Suhail, Mohd Khan, Ajmal Ahmad, Torki Zughaibi, Fohad Husain, Md Tabish Rehman, Shams Tabrez.

  Cancer is one of the leading causes of death worldwide. Even a slight decline in mortality has been noted, but the currently available treatment options did not give an expected outcome and are associated with several side effects and a substantial economic burden. The advent of plant-based treatment is because of its ease of use, readily availability, cost-effectiveness, and low/no toxicity. In recent years, flavonoids with their diverse physico-biological properties have gained the scientific community's attention for the treatment of various forms of cancer. Different flavonoids, especially; flavonols (quercetin, kaempferol, fisetin, and isorhamnetin), flavanones (hesperidin and naringin), and anthocyanins have shown potent anticancer activities. The role of various signaling cascades in the progression of cancer is also well-documented. Among those, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) signaling pathway is widely known to play a significant role in different physio-cellular activities, which triggers malignant transformation and is considered a key target for anticancer compounds. This pathway plays a vital role in regulating the cell cycle, metabolism, survival, and proliferation. The flavonoids exhibit their anticancer activity via different molecular pathways, including PI3K/Akt/mTOR. In the current piece of paper, our focus is to underpin the action of the above-mentioned flavonoids against different cancers, mainly covering in-vitro data, especially through PI3K/Akt/mTOR targeting.

Keywords:  Anthocyanins; cancer prevention; fisetin; flavanones; flavonols; hesperidin; isorhamnetin; kaempferol; mTOR; naringin; quercetin

DOI:  https://doi.org/10.2174/0929867328666210804091548
Cell Metab. 2021 Aug 03. pii: S1550-4131(21)00327-2. [Epub ahead of print]33(8): 1507-1509

Ending on a sour note: Lipids orchestrate ferroptosis in cancer.

Mike Lange, James A Olzmann.

Lipid metabolism is altered in the acidic tumor microenvironment. Here, the authors show that polyunsaturated fatty acid supplementation, together with concomitant inhibition of lipid droplet biogenesis, induces ferroptosis in acidic cancer cells. These findings highlight the potential to exploit cancer dependence on exogenous lipids as a therapeutic vulnerability.

DOI: https://doi.org/10.1016/j.cmet.2021.07.011
Metabolites. 2021 Jul 01. pii: 432. [Epub ahead of print]11(7):

Matrix Stiffness Modulates Metabolic Interaction between Human Stromal and Breast Cancer Cells to Stimulate Epithelial Motility.

Iván Ponce, Nelson Garrido, Nicolás Tobar, Francisco Melo, Patricio C Smith, Jorge Martínez.

  Breast tumors belong to the type of desmoplastic lesion in which a stiffer tissue structure is a determinant of breast cancer progression and constitutes a risk factor for breast cancer development. It has been proposed that cancer-associated stromal cells (responsible for this fibrotic phenomenon) are able to metabolize glucose via lactate production, which supports the catabolic metabolism of cancer cells. The aim of this work was to investigate the possible functional link between these two processes. To measure the effect of matrix rigidity on metabolic determinations, we used compliant elastic polyacrylamide gels as a substrate material, to which matrix molecules were covalently linked. We evaluated metabolite transport in stromal cells using two different FRET (Fluorescence Resonance Energy Transfer) nanosensors specific for glucose and lactate. Cell migration/invasion was evaluated using Transwell devices. We show that increased stiffness stimulates lactate production and glucose uptake by mammary fibroblasts. This response was correlated with the expression of stromal glucose transporter Glut1 and monocarboxylate transporters MCT4. Moreover, mammary stromal cells cultured on stiff matrices generated soluble factors that stimulated epithelial breast migration in a stiffness-dependent manner. Using a normal breast stromal cell line, we found that a stiffer extracellular matrix favors the acquisition mechanistical properties that promote metabolic reprograming and also constitute a stimulus for epithelial motility. This new knowledge will help us to better understand the complex relationship between fibrosis, metabolic reprogramming, and cancer malignancy.

Keywords:  breast cancer; lactate; monocarboxylate transporters; stiffness

DOI:  https://doi.org/10.3390/metabo11070432
Stem Cell Rev Rep. 2021 Aug 05.

Metabostemness in cancer: Linking metaboloepigenetics and mitophagy in remodeling cancer stem cells.

Prajna Paramita Naik, Swagatika Panigrahi, Ratnakar Parida, Prakash Priyadarshi Praharaj, Chandra Sekhar Bhol, Shankargouda Patil, Nml Manjunath, Dipanjan Ghosh, Samir Kumar Patra, Sujit Kumar Bhutia.

  Cancer stem cells (CSCs) are rare populations of malignant cells with stem cell-like features of self-renewal, uninterrupted differentiation, tumorigenicity, and resistance to conventional therapeutic agents, and these cells have a decisive role in treatment failure and tumor relapse. The self-renewal potential of CSCs with atypical activation of developmental signaling pathways involves the maintenance of stemness to support cancer progression. The acquisition of stemness in CSCs has been accomplished through genetic and epigenetic rewiring following the metabolic switch. In this context, "metabostemness" denotes the metabolic parameters that essentially govern the epitranscriptional gene reprogramming mechanism to dedifferentiate tumor cells into CSCs. Several metabolites often referred to as oncometabolites can directly remodel chromatin structure and thereby influence the operation of epitranscriptional circuits. This integrated metaboloepigenetic dimension of CSCs favors the differentiated cells to move in dedifferentiated macrostates. Some metabolic events might perform as early drivers of epitranscriptional reprogramming; however, subsequent metabolic hits may govern the retention of stemness properties in the tumor mass. Interestingly, selective removal of mitochondria through autophagy can promote metabolic plasticity and alter metabolic states during differentiation and dedifferentiation. In this connection, novel metabostemness-specific drugs can be generated as potential cancer therapeutics to target the metaboloepigenetic circuitry to eliminate CSCs.

Keywords:  Cancer Stem Cell; Metaboloepigenetics; Metabostemness; Mitophagy; Oncometabolism

DOI:  https://doi.org/10.1007/s12015-021-10216-9
Br J Nutr. 2021 Aug 02. 1-50

Potential of Olive oil and its phenolic compounds as therapeutic intervention against colorectal cancer: A comprehensive review.

Arindam Sain, Sakshi Sahu, Debdut Naskar.

  Colorectal cancer (CRC) is one of the major causes of death across the world and incidence rate of CRC increasing alarmingly each passing year. Diet, genomic anomalies, inflammation and deregulated signaling pathways are among the major causes of CRC. Because of numerous side effects of CRC therapies available now, researchers all over the world looking for alternative treatment/preventive strategy with lesser/no side effects. Olive oil which is part of Mediterranean diet contains numerous phenolic compounds that fight against free radicals and inflammation and also well-known for protective role against CRC. The current review focused on the recent evidences where olive oil and its phenolic compounds such as Hydroxytyrosol, Oleuropein and Oleocanthal showed activities against CRC as well to analyze the cellular and molecular signaling mechanism through which these compounds act on. These compounds shown to combat CRC by reducing proliferation, migration, invasion, and angiogenesis through regulation of numerous signaling pathways including MAPK pathway, PI3K-Akt pathway, and Wnt/β-catenin pathway etc. and at the same time induce apoptosis in different CRC model. However, further research is an absolute necessity to establish these compounds as nutritional supplements and develop therapeutic strategy in CRC.

Keywords:  Colorectal Cancer; Extra Virgin Olive Oil; Hydroxytyrosol; Oleocanthal; Oleuropein; Phytochemicals

DOI:  https://doi.org/10.1017/S0007114521002919
Chem Biol Interact. 2021 Jul 28. pii: S0009-2797(21)00240-4. [Epub ahead of print]347 109602

Metabolic reprograming confers tamoxifen resistance in breast cancer.

Alok Mishra, Anshuman Srivastava, Ankit Pateriya, Manendra Singh Tomar, Anand Kumar Mishra, Ashutosh Shrivastava.

  Breast cancer is the most common cancer among females and the leading cause of cancer-related deaths. Approximately 70 % of breast cancers are estrogen receptor (ER) positive. An ER antagonist such as tamoxifen is used as adjuvant therapy in ER-positive patients. The major problem with endocrine therapy is the emergence of acquired resistance in approximately 40 % of patients receiving tamoxifen. Metabolic alteration is one of the hallmarks of cancer cells. Rapidly proliferating cancer cells require increased nutritional support to fuel various functions such as proliferation, cell migration, and metastasis. Recent studies have established that the metabolic state of cancer cells influences their susceptibility to chemotherapeutic drugs and that cancer cells reprogram their metabolism to develop into resistant phenotypes. In this review, we discuss the major findings on metabolic pathway alterations in tamoxifen-resistant (TAMR) breast cancer and the molecular mechanisms known to regulate the expression and function of metabolic enzymes and the respective metabolite levels upon tamoxifen treatment. It is anticipated that this in-depth analysis of specific metabolic pathways in TAMR cancer might be exploited therapeutically.

Keywords:  Breast cancer; Estrogen receptor; Metabolism; Tamoxifen; Tamoxifen resistance

DOI:  https://doi.org/10.1016/j.cbi.2021.109602
Biomedicines. 2021 Jul 10. pii: 799. [Epub ahead of print]9(7):

IDH Mutations in Glioma: Double-Edged Sword in Clinical Applications?

Alisan Kayabolen, Ebru Yilmaz, Tugba Bagci-Onder.

  Discovery of point mutations in the genes encoding isocitrate dehydrogenases (IDH) in gliomas about a decade ago has challenged our view of the role of metabolism in tumor progression and provided a new stratification strategy for malignant gliomas. IDH enzymes catalyze the conversion of isocitrate to alpha-ketoglutarate (α-KG), an intermediate in the citric acid cycle. Specific mutations in the genes encoding IDHs cause neomorphic enzymatic activity that produces D-2-hydroxyglutarate (2-HG) and result in the inhibition of α-KG-dependent enzymes such as histone and DNA demethylases. Thus, chromatin structure and gene expression profiles in IDH-mutant gliomas appear to be different from those in IDH-wildtype gliomas. IDH mutations are highly common in lower grade gliomas (LGG) and secondary glioblastomas, and they are among the earliest genetic events driving tumorigenesis. Therefore, inhibition of mutant IDH enzymes in LGGs is widely accepted as an attractive therapeutic strategy. On the other hand, the metabolic consequences derived from IDH mutations lead to selective vulnerabilities within tumor cells, making them more sensitive to several therapeutic interventions. Therefore, instead of shutting down mutant IDH enzymes, exploiting the selective vulnerabilities caused by them might be another attractive and promising strategy. Here, we review therapeutic options and summarize current preclinical and clinical studies on IDH-mutant gliomas.

Keywords:  clinical trials; glioblastoma; glioma; isocitrate dehydrogenase (IDH); mutations; therapeutics

DOI:  https://doi.org/10.3390/biomedicines9070799
Adv Cancer Res. 2021 ;pii: S0065-230X(21)00033-6. [Epub ahead of print]152 383-413

Reductive stress in cancer.

Leilei Zhang, Kenneth D Tew.

  Reductive stress is defined as a condition characterized by excess accumulation of reducing equivalents (e.g., NADH, NADPH, GSH), surpassing the activity of endogenous oxidoreductases. Excessive reducing equivalents can perturb cell signaling pathways, change the formation of disulfide bonding in proteins, disturb mitochondrial homeostasis or decrease metabolism. Reductive stress is influenced by cellular antioxidant load, its flux and a subverted homeostasis that paradoxically can result in excess ROS induction. Balanced reducing equivalents and antioxidant enzymes that contribute to reductive stress can be regulated by Nrf2, typically considered as an oxidative stress induced transcription factor. Cancer cells may coordinate distinct pools of redox couples under reductive stress and these may link to biological consequences from both molecular and translational standpoints. In cancer, there is recent interest in understanding how selective induction of reductive stress may influence therapeutic management and disease progression.

Keywords:  Cellular homeostasis; GSH; NADH; NADPH; Oxidative stress; ROS; Reducing equivalents; Reductive stress

DOI:  https://doi.org/10.1016/bs.acr.2021.03.009
Cell Rep. 2021 Aug 03. pii: S2211-1247(21)00914-1. [Epub ahead of print]36(5): 109487

Ketogenesis impact on liver metabolism revealed by proteomics of lysine β-hydroxybutyrylation.

Kevin B Koronowski, Carolina M Greco, He Huang, Jin-Kwang Kim, Jennifer L Fribourgh, Priya Crosby, Lavina Mathur, Xuelian Ren, Carrie L Partch, Cholsoon Jang, Feng Qiao, Yingming Zhao, Paolo Sassone-Corsi.

  Ketone bodies are bioactive metabolites that function as energy substrates, signaling molecules, and regulators of histone modifications. β-hydroxybutyrate (β-OHB) is utilized in lysine β-hydroxybutyrylation (Kbhb) of histones, and associates with starvation-responsive genes, effectively coupling ketogenic metabolism with gene expression. The emerging diversity of the lysine acylation landscape prompted us to investigate the full proteomic impact of Kbhb. Global protein Kbhb is induced in a tissue-specific manner by a variety of interventions that evoke β-OHB. Mass spectrometry analysis of the β-hydroxybutyrylome in mouse liver revealed 891 sites of Kbhb within 267 proteins enriched for fatty acid, amino acid, detoxification, and one-carbon metabolic pathways. Kbhb inhibits S-adenosyl-L-homocysteine hydrolase (AHCY), a rate-limiting enzyme of the methionine cycle, in parallel with altered metabolite levels. Our results illuminate the role of Kbhb in hepatic metabolism under ketogenic conditions and demonstrate a functional consequence of this modification on a central metabolic enzyme.

Keywords:  AHCY; S-adenosyl-L-homocysteine hydrolase; ketogenesis; ketogenic diet; liver metabolism; lysine acylation; methionine cycle; β-hydroxybutyrate; β-hydroxybutyrylation

DOI:  https://doi.org/10.1016/j.celrep.2021.109487
Cancers (Basel). 2021 Aug 03. pii: 3906. [Epub ahead of print]13(15):

Inhibitors Targeting CDK9 Show High Efficacy against Osimertinib and AMG510 Resistant Lung Adenocarcinoma Cells.

Jaya Padmanabhan, Biswarup Saha, Chase Powell, Qianxing Mo, Bradford A Perez, Srikumar Chellappan.

  Non-small cell lung cancer has a 5-year survival rate of less than 12-15%, calling for the development of additional therapeutic strategies to combat this disease. Here we tested the efficacy of inhibiting cyclin-dependent kinase 9 (CDK9) on lung cancer cell lines with K-Ras and EGFR mutations and on lung cancer organoids. Three different CDK9 inhibitors reduced the viability and anchorage-independent growth of lung cancer cell lines at very low nanomolar to micromolar concentrations. CDK9 inhibition suppressed the expression of the anti-apoptotic protein, Mcl1, as well as the embryonic stem cell transcription factors, Sox2 and Sox9, which are pro-tumorigenic. In contrast, treatment with CDK9 inhibitors increased the levels of WT p53 and its downstream target p21 in K-Ras mutant cell lines. Furthermore, the CDK9 inhibitors could markedly reduce the viability of Osimertinib-resistant PC9 and AMG510-resistant H23 and H358 cells with comparable efficacy as the parental cells. CDK9 inhibitors could also significantly reduce the growth and viability of lung cancer organoids with high potency. Taken together, the data presented here strongly suggest that CDK9 inhibitors would be efficacious against K-Ras mutant and EGFR mutant NSCLCs, including those that develop resistance to targeted therapies.

Keywords:  BRD4; EGFR; K-RasG12C; lung cancer organoids; transcriptional CDKs

DOI:  https://doi.org/10.3390/cancers13153906
Expert Opin Drug Metab Toxicol. 2021 Aug 04.

Cytotoxic activity of KRAS inhibitors in combination with chemotherapeutics.

Gerhard Hamilton, Adelina Plangger.

  Introduction: KRAS is the most frequently mutated oncogenic driver in pancreatic, lung and colon cancer. Recently, KRAS inhibitors in clinical use show promising activity but most responses are partial and drug resistance develops. The use of therapeutics in combination with KRAS inhibitors are expected to improve outcomes.Areas covered: This review describes the KRAS G12C mutation-specific inhibitors and the SOS1-targeting inhibitors that reduce the GTP- loading of wildtype and mutated KRAS. Both types of compounds reduce tumor cell proliferation in vitro and in vivo. The combinations of the various KRAS inhibitors with downstream signaling effectors, modulators of KRAS-associated metabolic alterations and chemotherapeutics are summarized.Expert opinion: The clinical potency of mutated KRAS-specific inhibitors needs to be improved by suitable drug combinations. Inhibition of downstream signaling cascades increases toxicity and other combinations exploited comprise G12C-directed inhibitors with SOS1 inhibitors, glucose/glutamine metabolic modulators, classical chemotherapeutics and others. The most suitable inhibitor combinations corroborated in preclinical development await clinical verification.

Keywords:  Cancer; amg510; combination therapy; g12c; kras; mrtx849; sos1 inhibitor

DOI:  https://doi.org/10.1080/17425255.2021.1965123
Cell Rep Med. 2021 Jul 20. 2(7): 100350

ASN007 is a selective ERK1/2 inhibitor with preferential activity against RAS-and RAF-mutant tumors.

Ana Portelinha, Scott Thompson, Roger A Smith, Mariana Da Silva Ferreira, Zahra Asgari, Andrea Knezevic, Venkatraman Seshan, Elisa de Stanchina, Sandeep Gupta, Louis Denis, Anas Younes, Sanjeeva Reddy.

  Inhibition of the extracellular signal-regulated kinases ERK1 and ERK2 (ERK1/2) offers a promising therapeutic strategy in cancers harboring activated RAS/RAF/MEK/ERK signaling pathways. Here, we describe an orally bioavailable and selective ERK1/2 inhibitor, ASN007, currently in clinical development for the treatment of cancer. In preclinical studies, ASN007 shows strong antiproliferative activity in tumors harboring mutations in BRAF and RAS (KRAS, NRAS, and HRAS). ASN007 demonstrates activity in a BRAFV600E mutant melanoma tumor model that is resistant to BRAF and MEK inhibitors. The PI3K inhibitor copanlisib enhances the antiproliferative activity of ASN007 both in vitro and in vivo due to dual inhibition of RAS/MAPK and PI3K survival pathways. Our data provide a rationale for evaluating ASN007 in RAS/RAF-driven tumors as well as a mechanistic basis for combining ASN007 with PI3K inhibitors.

Keywords:  ASN007; ERK; KRAS; PI3K; RAF/RAS-driven cancers; biomarker; combinational therapy; kinase inhibitor; lymphoma; solid tumors

DOI:  https://doi.org/10.1016/j.xcrm.2021.100350
Cancer Res. 2021 Aug 04. pii: canres.0753.2021. [Epub ahead of print]

Hypoxia promotes breast cancer cell growth by activating a glycogen metabolic program.

Ke Tang, Liyan Zhu, Jie Chen, Dianheng Wang, Liping Zeng, Chen Chen, Liang Tang, Li Zhou, Keke Wei, Yabo Zhou, Jiadi Lv, Yuying Liu, Huafeng Zhang, Jingwei Ma, Bo Huang.

Hypoxia is known to be commonly present in breast tumor microenvironments. Stem-like cells that repopulate breast tumors, termed tumor-repopulating cells (TRC), thrive under hypoxic conditions, but the underlying mechanism remains unclear. Here we show that hypoxia promotes the growth of breast TRCs through metabolic reprogramming. Hypoxia mobilized transcription factors HIF-1α and FoxO1 and induced epigenetic reprogramming to upregulate cytosolic phosphoenolpyruvate carboxykinase (PCK1), a key enzyme that initiates gluconeogenesis. PCK1 subsequently triggered retrograde carbon flow from gluconeogenesis to glycogenesis, glycogenolysis, and the pentose phosphate pathway. The resultant NADPH facilitated reduced glutathione production, leading to a moderate increase of reactive oxygen species that stimulated hypoxic breast TRC growth. Notably, this metabolic mechanism was absent in differentiated breast tumor cells. Targeting PCK1 synergized with paclitaxel to reduce the growth of triple-negative breast cancer (TNBC). These findings uncover an altered glycogen metabolic program in breast cancer, providing potential metabolic strategies to target hypoxic breast TRCs and TNBC.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-0753
Int J Mol Sci. 2021 Jul 21. pii: 7787. [Epub ahead of print]22(15):

The Green Anti-Cancer Weapon. The Role of Natural Compounds in Bladder Cancer Treatment.

Paulina Wigner, Michal Bijak, Joanna Saluk-Bijak.

  Bladder cancer (BC) is the second most common genitourinary cancer. In 2018, 550,000 people in the world were diagnosed with BC, and the number of new cases continues to rise. BC is also characterized by high recurrence risk, despite therapies. Although in the last few years, the range of BC therapy has considerably widened, it is associated with severe side effects and the development of drug resistance, which is hampering treatment success. Thus, patients are increasingly choosing products of natural origin as an alternative or complementary therapeutic options. Therefore, in this article, we aim to elucidate, using the available literature, the role of natural substances such as curcumin, sulforaphane, resveratrol, quercetin, 6-gingerol, delphinidin, epigallocatechin-3-gallate and gossypol in the BC treatment. Numerous clinical and preclinical studies point to their role in the modulation of the signaling pathways, such as cell proliferation, cell survival, apoptosis and cell death.

Keywords:  6-gingerol; bladder cancer treatment; curcumin; delphinidin; epigallocatechin-3-gallate; gossypol; quercetin; resveratrol; sulforaphane

DOI:  https://doi.org/10.3390/ijms22157787
Cancer Biol Med. 2021 Aug 04. pii: j.issn.2095-3941.2020.0532. [Epub ahead of print]

Efficacy of rigosertib, a small molecular RAS signaling disrupter for the treatment of KRAS-mutant colorectal cancer.

Xinyi Zhou, Qian Xiao, Dongliang Fu, Haochen Zhang, Yang Tang, Jinjie He, Yeting Hu, Xiangxing Kong, Fei Teng, Xiangrui Liu, Ying Yuan, Kefeng Ding.

  OBJECTIVE: Mutant KRAS, the principal isoform of RAS, plays a pivotal role in the oncogenesis of colorectal cancer by constitutively activating the RAF/MEK/ERK and PI3K/AKT pathways. Effective targeted therapies are urgently needed. We investigated whether rigosertib, a benzyl styryl sulfone RAS signaling disruptor, could selectively kill KRAS-mutant colorectal cancer cells.METHODS: CCK-8 was used to determine the cell viability. Patient-derived tumor and cancer cell xenograft models were used to detect the inhibitory efficacy of rigosertib. Flow cytometry was used to evaluate the apoptosis and cell cycle progression. Apoptosis and cell cycle arrest markers were detected by Western blot. DCFH-DA was used to determine the reactive oxygen species. Immunohistochemistry staining and Western blot were performed to characterize RAS signaling markers in colorectal cancer tissues and cells.
RESULTS: Rigosertib (RGS) exhibited a cytotoxic effect against colorectal cancer cells, which was greater in KRAS-mutant cells. Furthermore, RGS induced mitotic arrest and oxidative stress-dependent apoptosis in KRAS-mutant DLD1 and HCT116 cells. Besides, RGS disrupted RAS signaling, and the inhibition of RAS/MEK/ERK was independent of cellular oxidative stress. Using patient-derived xenograft models, the response and tumor inhibition of RGS were significantly higher in the KRAS-mutant subgroup, while p-MEK, p-ERK, and p-AKT levels of RGS-treated tumors were significantly decreased. Finally, in a KRAS-mutant, chemotherapy-resistant patient-derived xenograft model, RGS showed a stronger therapeutic effect than the combination standard therapy involving fluoropyrimidine + oxaliplatin/irinotecan + bevacizumab.
CONCLUSIONS: These data showed that targeting RAS signaling using RGS could be a therapeutic treatment for KRAS-mutant colorectal cancer patients.

Keywords:  Colorectal cancer; KRAS mutation; RAS signaling; rigosertib; therapeutic effect

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2020.0532
Phytomedicine. 2021 Jul 18. pii: S0944-7113(21)00217-8. [Epub ahead of print]91 153674

Physciosporin suppresses mitochondrial respiration, aerobic glycolysis, and tumorigenesis in breast cancer.

İsa Taş, Mücahit Varlı, Yeseon Son, Jin Han, Dahye Kwak, Yi Yang, Rui Zhou, Chathurika D B Gamage, Sultan Pulat, So-Yeon Park, Young Hyun Yu, Kyung-Sub Moon, Kyung-Hwa Lee, Hyung-Ho Ha, Jae-Seoun Hur, Hangun Kim.

  BACKGROUND: Physciosporin (PHY) is one of the potent anticancer lichen compound. Recently, PHY was shown to suppress colorectal cancer cell proliferation, motility, and tumorigenesis through novel mechanisms of action.PURPOSE: We investigated the effects of PHY on energy metabolism and tumorigenicity of the human breast cancer (BC) cells MCF-7 (estrogen and progesterone positive BC) and MDA-MB-231 (triple negative BC).
METHODS: The anticancer effect of PHY on cell viability, motility, cancer metabolism and tumorigenicity was evaluated by MTT assay, migration assay, clonogenic assay, anchorage-independent colony formation assay, glycolytic and mitochondrial metabolism analysis, qRT-PCR, flow cytometric analysis, Western blotting, immunohistochemistry in vitro; and by tumorigenicity study with orthotopic breast cancer xenograft model in vivo.
RESULTS: PHY markedly inhibited BC cell viability. Cell-cycle profiling and Annexin V-FITC/PI double staining showed that a toxic dosage of PHY triggered apoptosis in BC cell lines by regulating the B-cell lymphoma-2 (Bcl-2) family proteins and the activity of caspase pathway. At non-toxic concentrations, PHY potently decreased migration, proliferation, and tumorigenesis of BC cells in vitro. Metabolic studies revealed that PHY treatment significantly reduced the bioenergetic profile by decreasing respiration, ATP production, and glycolysis capacity. In addition, PHY significantly altered the levels of mitochondrial (PGC-1α) and glycolysis (GLUT1, HK2 and PKM2) markers, and downregulated transcriptional regulators involved in cancer cell metabolism, including β-catenin, c-Myc, HIF-1α, and NF-κB. An orthotopic implantation mouse model of BC confirmed that PHY treatment suppressed BC growth in vivo and target genes were consistently suppressed in tumor specimens.
CONCLUSION: The findings from our in vitro as well as in vivo studies exhibit that PHY suppresses energy metabolism as well as tumorigenesis in BC. Especially, PHY represents a promising therapeutic effect against hormone-insensitive BC (triple negative) by targeting energy metabolism.

Keywords:  Anticancer; Breast cancer; Cancer metabolism; Energy metabolism; Lichen; Natural product

DOI:  https://doi.org/10.1016/j.phymed.2021.153674
Genes (Basel). 2021 Jul 19. pii: 1094. [Epub ahead of print]12(7):

The Importance of Being PI3K in the RAS Signaling Network.

Cristina Cuesta, Cristina Arévalo-Alameda, Esther Castellano.

  Ras proteins are essential mediators of a multitude of cellular processes, and its deregulation is frequently associated with cancer appearance, progression, and metastasis. Ras-driven cancers are usually aggressive and difficult to treat. Although the recent Food and Drug Administration (FDA) approval of the first Ras G12C inhibitor is an important milestone, only a small percentage of patients will benefit from it. A better understanding of the context in which Ras operates in different tumor types and the outcomes mediated by each effector pathway may help to identify additional strategies and targets to treat Ras-driven tumors. Evidence emerging in recent years suggests that both oncogenic Ras signaling in tumor cells and non-oncogenic Ras signaling in stromal cells play an essential role in cancer. PI3K is one of the main Ras effectors, regulating important cellular processes such as cell viability or resistance to therapy or angiogenesis upon oncogenic Ras activation. In this review, we will summarize recent advances in the understanding of Ras-dependent activation of PI3K both in physiological conditions and cancer, with a focus on how this signaling pathway contributes to the formation of a tumor stroma that promotes tumor cell proliferation, migration, and spread.

Keywords:  PI3-Kinase; Ras oncogenes

DOI:  https://doi.org/10.3390/genes12071094