bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2021–07–25
23 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Emerging strategies to target RAS signaling in human cancer therapy.
  2. Amino acid metabolism as a therapeutic target in cancer: a review.
  3. Proline metabolism and redox; maintaining a balance in health and disease.
  4. Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?
  5. Cisplatin Resistance and Redox-Metabolic Vulnerability: A Second Alteration.
  6. Ketogenic Diet in Cancer Prevention and Therapy: Molecular Targets and Therapeutic Opportunities.
  7. Mitochondrial Metabolism in Carcinogenesis and Cancer Therapy.
  8. Proteomics-based target identification of natural products affecting cancer metabolism.
  9. Inhibitory Potential of Dietary Nutraceuticals on Cellular PI3K/Akt Signaling: Implications in Cancer Prevention and Therapy.
  10. Targeting the PI3K/AKT/mTOR Signaling Pathway in Lung Cancer: An Update Regarding Potential Drugs and Natural Products.
  11. Curcumin: Modulator of Key Molecular Signaling Pathways in Hormone-Independent Breast Cancer.
  12. Targeting cancer stem cells by nutraceuticals for cancer therapy.
  13. Arginine Signaling and Cancer Metabolism.
  14. Targeting Glucose Metabolism of Cancer Cells with Dichloroacetate to Radiosensitize High-Grade Gliomas.
  15. Reactive oxygen species in cancer: current findings and future directions.
  16. Metabolic landscapes in sarcomas.
  17. Identification of a Small-Molecule Glucose Transporter Inhibitor, Glutipyran, That Inhibits Cancer Cell Growth.
  18. One carbon metabolism in human lung cancer.
  19. AMPK-deficiency forces metformin-challenged cancer cells to switch from carbohydrate metabolism to ketogenesis to support energy metabolism.
  20. Proline dehydrogenase in cancer: apoptosis, autophagy, nutrient dependency and cancer therapy.
  21. An enhanced chemopreventive effect of methyl donor S-adenosylmethionine in combination with 25-hydroxyvitamin D in blocking mammary tumor growth and metastasis.
  22. Tumor microenvironment: a prospective target of natural alkaloids for cancer treatment.
  23. SILAC-based quantitative MS approach reveals Withaferin A regulated proteins in prostate cancer.
  1. J Hematol Oncol. 2021 Jul 23. 14(1): 116
    Emerging strategies to target RAS signaling in human cancer therapy.
    Kun Chen, Yalei Zhang, Ling Qian, Peng Wang.
      RAS mutations (HRAS, NRAS, and KRAS) are among the most common oncogenes, and around 19% of patients with cancer harbor RAS mutations. Cells harboring RAS mutations tend to undergo malignant transformation and exhibit malignant phenotypes. The mutational status of RAS correlates with the clinicopathological features of patients, such as mucinous type and poor differentiation, as well as response to anti-EGFR therapies in certain types of human cancers. Although RAS protein had been considered as a potential target for tumors with RAS mutations, it was once referred to as a undruggable target due to the consecutive failure in the discovery of RAS protein inhibitors. However, recent studies on the structure, signaling, and function of RAS have shed light on the development of RAS-targeting drugs, especially with the approval of Lumakras (sotorasib, AMG510) in treatment of KRASG12C-mutant NSCLC patients. Therefore, here we fully review RAS mutations in human cancer and especially focus on emerging strategies that have been recently developed for RAS-targeting therapy.
    Keywords:  Clinicopathological features; Hotspots; RAS mutations; RAS-targeted therapy
    DOI:  https://doi.org/10.1186/s13045-021-01127-w
  2. Amino Acids. 2021 Jul 22.
    Amino acid metabolism as a therapeutic target in cancer: a review.
    Molly Endicott, Michael Jones, Jonathon Hull.
      Malignant cells often demonstrate a proliferative advantage when compared to non-malignant cells. However, the rapid growth and metabolism required for survival can also highlight vulnerabilities specific to these malignant cells. One such vulnerability exhibited by cancer is an increased demand for amino acids (AAs), which often results in a dependency on exogenous sources of AAs or requires upregulation of de novo synthesis. These metabolic alterations can be exploited by therapy, which aims to improve treatment outcome and decrease relapse and reoccurrence. One clinically utilised strategy targeting AA dependency is the use of asparaginase in the treatment of acute lymphoblastic leukaemia (ALL), which results in a depletion of exogenous asparagine and subsequent cancer cell death. Examples of other successful strategies include the exploitation of arginine deiminase and methioninase, nutrient restriction of methionine and the inhibition of glutaminase. In this review, we summarise these treatment strategies into three promising avenues: AA restriction, enzymatic depletion and inhibition of metabolism. This review provides an insight into the complexity of metabolism in cancer, whilst highlighting these three current research avenues that have support in both preclinical and clinical settings.
    Keywords:  Amino acids; Asparaginase; Cancer; Metabolism; Oncology
    DOI:  https://doi.org/10.1007/s00726-021-03052-1
  3. Amino Acids. 2021 Jul 22.
    Proline metabolism and redox; maintaining a balance in health and disease.
    Lisa A Vettore, Rebecca L Westbrook, Daniel A Tennant.
      Proline is a non-essential amino acid with key roles in protein structure/function and maintenance of cellular redox homeostasis. It is available from dietary sources, generated de novo within cells, and released from protein structures; a noteworthy source being collagen. Its catabolism within cells can generate ATP and reactive oxygen species (ROS). Recent findings suggest that proline biosynthesis and catabolism are essential processes in disease; not only due to the role in new protein synthesis as part of pathogenic processes but also due to the impact of proline metabolism on the wider metabolic network through its significant role in redox homeostasis. This is particularly clear in cancer proliferation and metastatic outgrowth. Nevertheless, the precise identity of the drivers of cellular proline catabolism and biosynthesis, and the overall cost of maintaining appropriate balance is not currently known. In this review, we explore the major drivers of proline availability and consumption at a local and systemic level with a focus on cancer. Unraveling the main factors influencing proline metabolism in normal physiology and disease will shed light on new effective treatment strategies.
    Keywords:  Cancer; Disease; Proline; Redox
    DOI:  https://doi.org/10.1007/s00726-021-03051-2
  4. Cancers (Basel). 2021 Jul 03. pii: 3351. [Epub ahead of print]13(13):
    Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?
    Christopher McCann, Emma M Kerr.
      Drug resistance is a major cause of cancer treatment failure, effectively driven by processes that promote escape from therapy-induced cell death. The mechanisms driving evasion of apoptosis have been widely studied across multiple cancer types, and have facilitated new and exciting therapeutic discoveries with the potential to improve cancer patient care. However, an increasing understanding of the crosstalk between cancer hallmarks has highlighted the complexity of the mechanisms of drug resistance, co-opting pathways outside of the canonical "cell death" machinery to facilitate cell survival in the face of cytotoxic stress. Rewiring of cellular metabolism is vital to drive and support increased proliferative demands in cancer cells, and recent discoveries in the field of cancer metabolism have uncovered a novel role for these programs in facilitating drug resistance. As a key organelle in both metabolic and apoptotic homeostasis, the mitochondria are at the forefront of these mechanisms of resistance, coordinating crosstalk in the event of cellular stress, and promoting cellular survival. Importantly, the appreciation of this role metabolism plays in the cytotoxic response to therapy, and the ability to profile metabolic adaptions in response to treatment, has encouraged new avenues of investigation into the potential of exploiting metabolic addictions to improve therapeutic efficacy and overcome drug resistance in cancer. Here, we review the role cancer metabolism can play in mediating drug resistance, and the exciting opportunities presented by imposed metabolic vulnerabilities.
    Keywords:  cancer metabolism; cell death; drug resistance; mitochondria
    DOI:  https://doi.org/10.3390/cancers13133351
  5. Int J Mol Sci. 2021 Jul 09. pii: 7379. [Epub ahead of print]22(14):
    Cisplatin Resistance and Redox-Metabolic Vulnerability: A Second Alteration.
    Medhi Wangpaichitr, George Theodoropoulos, Dan J M Nguyen, Chunjing Wu, Sydney A Spector, Lynn G Feun, Niramol Savaraj.
      The development of drug resistance in tumors is a major obstacle to effective cancer chemotherapy and represents one of the most significant complications to improving long-term patient outcomes. Despite early positive responsiveness to platinum-based chemotherapy, the majority of lung cancer patients develop resistance. The development of a new combination therapy targeting cisplatin-resistant (CR) tumors may mark a major improvement as salvage therapy in these patients. The recent resurgence in research into cellular metabolism has again confirmed that cancer cells utilize aerobic glycolysis ("the Warburg effect") to produce energy. Hence, this observation still remains a characteristic hallmark of altered metabolism in certain cancer cells. However, recent evidence promotes another concept wherein some tumors that acquire resistance to cisplatin undergo further metabolic alterations that increase tumor reliance on oxidative metabolism (OXMET) instead of glycolysis. Our review focuses on molecular changes that occur in tumors due to the relationship between metabolic demands and the importance of NAD+ in redox (ROS) metabolism and the crosstalk between PARP-1 (Poly (ADP ribose) polymerase-1) and SIRTs (sirtuins) in CR tumors. Finally, we discuss a role for the tumor metabolites of the kynurenine pathway (tryptophan catabolism) as effectors of immune cells in the tumor microenvironment during acquisition of resistance in CR cells. Understanding these concepts will form the basis for future targeting of CR cells by exploiting redox-metabolic changes and their consequences on immune cells in the tumor microenvironment as a new approach to improve overall therapeutic outcomes and survival in patients who fail cisplatin.
    Keywords:  cisplatin resistance; metabolism; oxidative metabolism; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms22147379
  6. Curr Issues Mol Biol. 2021 Jul 03. 43(2): 558-589
    Ketogenic Diet in Cancer Prevention and Therapy: Molecular Targets and Therapeutic Opportunities.
    Wamidh H Talib, Asma Ismail Mahmod, Ayah Kamal, Hasan M Rashid, Aya M D Alashqar, Samar Khater, Duaa Jamal, Mostafa Waly.
      Although cancer is still one of the most significant global challenges facing public health, the world still lacks complementary approaches that would significantly enhance the efficacy of standard anticancer therapies. One of the essential strategies during cancer treatment is following a healthy diet program. The ketogenic diet (KD) has recently emerged as a metabolic therapy in cancer treatment, targeting cancer cell metabolism rather than a conventional dietary approach. The ketogenic diet (KD), a high-fat and very-low-carbohydrate with adequate amounts of protein, has shown antitumor effects by reducing energy supplies to cells. This low energy supply inhibits tumor growth, explaining the ketogenic diet's therapeutic mechanisms in cancer treatment. This review highlights the crucial mechanisms that explain the ketogenic diet's potential antitumor effects, which probably produces an unfavorable metabolic environment for cancer cells and can be used as a promising adjuvant in cancer therapy. Studies discussed in this review provide a solid background for researchers and physicians to design new combination therapies based on KD and conventional therapies.
    Keywords:  alternative cancer therapies; anticancer diet; calories restriction; targeting cancer metabolism
    DOI:  https://doi.org/10.3390/cimb43020042
  7. Cancers (Basel). 2021 Jul 01. pii: 3311. [Epub ahead of print]13(13):
    Mitochondrial Metabolism in Carcinogenesis and Cancer Therapy.
    Hadia Moindjie, Sylvie Rodrigues-Ferreira, Clara Nahmias.
      Carcinogenesis is a multi-step process that refers to transformation of a normal cell into a tumoral neoplastic cell. The mechanisms that promote tumor initiation, promotion and progression are varied, complex and remain to be understood. Studies have highlighted the involvement of oncogenic mutations, genomic instability and epigenetic alterations as well as metabolic reprogramming, in different processes of oncogenesis. However, the underlying mechanisms still have to be clarified. Mitochondria are central organelles at the crossroad of various energetic metabolisms. In addition to their pivotal roles in bioenergetic metabolism, they control redox homeostasis, biosynthesis of macromolecules and apoptotic signals, all of which are linked to carcinogenesis. In the present review, we discuss how mitochondria contribute to the initiation of carcinogenesis through gene mutations and production of oncometabolites, and how they promote tumor progression through the control of metabolic reprogramming and mitochondrial dynamics. Finally, we present mitochondrial metabolism as a promising target for the development of novel therapeutic strategies.
    Keywords:  ROS; Warburg effect; carcinogenesis; metabolic reprogramming; mitochondria; mitochondrial oxidative respiration; mitophagy; mtDNA mutations; oncometabolites; therapy
    DOI:  https://doi.org/10.3390/cancers13133311
  8. J Antibiot (Tokyo). 2021 Jul 20.
    Proteomics-based target identification of natural products affecting cancer metabolism.
    Makoto Muroi, Hiroyuki Osada.
      The Warburg effect, a widely known characteristic of cancer cells, refers to the utilization of glycolysis under aerobic conditions for extended periods of time. Recent studies have revealed that cancer cells are capable of reprogramming their metabolic pathways to meet vigorous metabolic demands. New anticancer drugs that target the complicated metabolic systems of cancer cells are being developed. Identifying the potential targets of novel compounds that affect cancer metabolism may enable the discovery of new therapeutic targets for cancer treatment, and hasten the development of anticancer drugs. Historically, various drug screening techniques such as the analysis of a compound's antiproliferative effect on cancer cells and proteomic methods, that enable target identification have been used to obtain many useful drugs from natural products. Here, we review proteomics-based target identification methods applicable to natural products that affect cancer metabolism.
    DOI:  https://doi.org/10.1038/s41429-021-00437-y
  9. Curr Top Med Chem. 2021 Jul 16.
    Inhibitory Potential of Dietary Nutraceuticals on Cellular PI3K/Akt Signaling: Implications in Cancer Prevention and Therapy.
    Arunaksharan Narayanankutty.
       BACKGROUND: The phosphatidyl inositol-3 kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) signaling have been associated with many cellular physiological events such as proliferation, maturation, survival, and metabolism. Besides their roles in normal cells, the pathway is often upregulated in various cancers. Due to their prominent roles in the cancer progression events, it is now being considered a target for cancer therapy and cancer chemoprevention.
    OBJECTIVES: The present review provides a concise outline of the role of the PI3K/Akt/mTOR pathway in carcinogenesis and progression events, including metastasis, drug resistance, and stemness. Further, emphasis is given to the PI3K/Akt/mTOR pathway inhibitory potentials of various food-derived bioactive components in cancer prevention.
    METHODS: Data on the PI3K/Akt/mTOR inhibiting natural products and their bioactive compounds have been obtained from PubMed/Medline, Scopus, Eurekaselect, etc. Findings from the above citation databases from 2000-2021 are included in the manuscript.
    RESULTS: Numerous compounds from plants have been isolated and identified as anticancer agents; among these, a predominant class is nutraceuticals. The PI3K pathway is the principal target of these natural products, and many of these drug candidates are under various stages of drug development. These compounds have shown a significant inhibitory effect on the kinase activities of PI3K and Akt, resulting in the abrogation of cancer initiation and progression events. In addition, these compounds have been shown to reverse the resistance to chemotherapeutic drugs and reduce the population of cancer stem cells.
    CONCLUSION: The nutraceuticals are promising candidates as anticancer agents by blocking PI3K signaling cascades. As the PI3K is a central pathway to various receptor signaling, the dietary intervention may prove highly effective.
    Keywords:  Dietary bioactive components; Drug resistance; Metastasis; PI3K/Akt/mTOR pathway; anticancer activity; cancer; functional food
    DOI:  https://doi.org/10.2174/1568026621666210716152224
  10. Molecules. 2021 Jul 05. pii: 4100. [Epub ahead of print]26(13):
    Targeting the PI3K/AKT/mTOR Signaling Pathway in Lung Cancer: An Update Regarding Potential Drugs and Natural Products.
    Iksen, Sutthaorn Pothongsrisit, Varisa Pongrakhananon.
      Lung cancer is one of the most common cancers and has a high mortality rate. Due to its high incidence, the clinical management of the disease remains a major challenge. Several reports have documented a relationship between the phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway and lung cancer. The recognition of this pathway as a notable therapeutic target in lung cancer is mainly due to its central involvement in the initiation and progression of the disease. Interest in using natural and synthetic medications to target these signaling pathways has increased in recent years, with promising results in vitro, in vivo, and in clinical trials. In this review, we focus on the current understanding of PI3K/AKT/mTOR signaling in tumor development. In addition to the signaling pathway, we highlighted the therapeutic potential of recently developed PI3K/AKT/mTOR inhibitors based on preclinical and clinical trials.
    Keywords:  mammalian target of rapamycin (mTOR); natural compounds; phosphatidylinositol-3-kinase (PI3K); protein kinase B (PKB/AKT)
    DOI:  https://doi.org/10.3390/molecules26134100
  11. Cancers (Basel). 2021 Jul 08. pii: 3427. [Epub ahead of print]13(14):
    Curcumin: Modulator of Key Molecular Signaling Pathways in Hormone-Independent Breast Cancer.
    Reyhaneh Farghadani, Rakesh Naidu.
      Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women worldwide. Despite the overall successes in breast cancer therapy, hormone-independent HER2 negative breast cancer, also known as triple negative breast cancer (TNBC), lacking estrogens and progesterone receptors and with an excessive expression of human epidermal growth factor receptor 2 (HER2), along with the hormone-independent HER2 positive subtype, still remain major challenges in breast cancer treatment. Due to their poor prognoses, aggressive phenotype, and highly metastasis features, new alternative therapies have become an urgent clinical need. One of the most noteworthy phytochemicals, curcumin, has attracted enormous attention as a promising drug candidate in breast cancer prevention and treatment due to its multi-targeting effect. Curcumin interrupts major stages of tumorigenesis including cell proliferation, survival, angiogenesis, and metastasis in hormone-independent breast cancer through the modulation of multiple signaling pathways. The current review has highlighted the anticancer activity of curcumin in hormone-independent breast cancer via focusing on its impact on key signaling pathways including the PI3K/Akt/mTOR pathway, JAK/STAT pathway, MAPK pathway, NF-ĸB pathway, p53 pathway, and Wnt/β-catenin, as well as apoptotic and cell cycle pathways. Besides, its therapeutic implications in clinical trials are here presented.
    Keywords:  HER2; breast cancer; chemotherapy and chemoprevention; clinical trial; curcumin; hormone-independent; phytochemical; polyphenol; signaling pathway; triple negative
    DOI:  https://doi.org/10.3390/cancers13143427
  12. Semin Cancer Biol. 2021 Jul 14. pii: S1044-579X(21)00202-9. [Epub ahead of print]
    Targeting cancer stem cells by nutraceuticals for cancer therapy.
    Man Chu, Cheng Zheng, Cheng Chen, Gendi Song, Xiaoli Hu, Zhi-Wei Wang.
      Accumulating evidence has demonstrated that cancer stem cells (CSCs) play an essential role in tumor progression and reoccurrence and drug resistance. Multiple signaling pathways have been revealed to be critically participated in CSC development and maintenance. Emerging evidence indicates that numerous chemopreventive compounds, also known as nutraceuticals, could eliminate CSCs in part via regulating several signaling pathways. Therefore, in this review, we will describe the some natural chemopreventive agents that target CSCs in a variety of human malignancies, including soy isoflavone, curcumin, resveratrol, tea polyphenols, sulforaphane, quercetin, indole-3-carbinol, 3,3'-diindolylmethane, withaferin A, apigenin, etc. Moreover, we discuss that eliminating CSCs by nutraceuticals might be a promising strategy for treating human cancer via overcoming drug resistance and reducing tumor reoccurrence.
    Keywords:  Cancer; Cancer therapy; Natural agents; Signaling pathways; Stem cell
    DOI:  https://doi.org/10.1016/j.semcancer.2021.07.008
  13. Cancers (Basel). 2021 Jul 15. pii: 3541. [Epub ahead of print]13(14):
    Arginine Signaling and Cancer Metabolism.
    Chia-Lin Chen, Sheng-Chieh Hsu, David K Ann, Yun Yen, Hsing-Jien Kung.
      Arginine is an amino acid critically involved in multiple cellular processes including the syntheses of nitric oxide and polyamines, and is a direct activator of mTOR, a nutrient-sensing kinase strongly implicated in carcinogenesis. Yet, it is also considered as a non- or semi-essential amino acid, due to normal cells' intrinsic ability to synthesize arginine from citrulline and aspartate via ASS1 (argininosuccinate synthase 1) and ASL (argininosuccinate lyase). As such, arginine can be used as a dietary supplement and its depletion as a therapeutic strategy. Strikingly, in over 70% of tumors, ASS1 transcription is suppressed, rendering the cells addicted to external arginine, forming the basis of arginine-deprivation therapy. In this review, we will discuss arginine as a signaling metabolite, arginine's role in cancer metabolism, arginine as an epigenetic regulator, arginine as an immunomodulator, and arginine as a therapeutic target. We will also provide a comprehensive summary of ADI (arginine deiminase)-based arginine-deprivation preclinical studies and an update of clinical trials for ADI and arginase. The different cell killing mechanisms associated with various cancer types will also be described.
    Keywords:  ADI; arginase; arginine; arginine-deprivation therapy; cancer metabolism; epigenetics
    DOI:  https://doi.org/10.3390/cancers13143541
  14. Int J Mol Sci. 2021 Jul 06. pii: 7265. [Epub ahead of print]22(14):
    Targeting Glucose Metabolism of Cancer Cells with Dichloroacetate to Radiosensitize High-Grade Gliomas.
    Kristina M Cook, Han Shen, Kelly J McKelvey, Harriet E Gee, Eric Hau.
      As the cornerstone of high-grade glioma (HGG) treatment, radiotherapy temporarily controls tumor cells via inducing oxidative stress and subsequent DNA breaks. However, almost all HGGs recur within months. Therefore, it is important to understand the underlying mechanisms of radioresistance, so that novel strategies can be developed to improve the effectiveness of radiotherapy. While currently poorly understood, radioresistance appears to be predominantly driven by altered metabolism and hypoxia. Glucose is a central macronutrient, and its metabolism is rewired in HGG cells, increasing glycolytic flux to produce energy and essential metabolic intermediates, known as the Warburg effect. This altered metabolism in HGG cells not only supports cell proliferation and invasiveness, but it also contributes significantly to radioresistance. Several metabolic drugs have been used as a novel approach to improve the radiosensitivity of HGGs, including dichloroacetate (DCA), a small molecule used to treat children with congenital mitochondrial disorders. DCA reverses the Warburg effect by inhibiting pyruvate dehydrogenase kinases, which subsequently activates mitochondrial oxidative phosphorylation at the expense of glycolysis. This effect is thought to block the growth advantage of HGGs and improve the radiosensitivity of HGG cells. This review highlights the main features of altered glucose metabolism in HGG cells as a contributor to radioresistance and describes the mechanism of action of DCA. Furthermore, we will summarize recent advances in DCA's pre-clinical and clinical studies as a radiosensitizer and address how these scientific findings can be translated into clinical practice to improve the management of HGG patients.
    Keywords:  cancer metabolism; dichloroacetate; glycolysis; high-grade gliomas; hypoxia; radioresistance; radiotherapy
    DOI:  https://doi.org/10.3390/ijms22147265
  15. Cancer Sci. 2021 Jul 19.
    Reactive oxygen species in cancer: current findings and future directions.
    Hajime Nakamura, Kohichi Takada.
      Reactive oxygen species (ROS), a class of highly bioactive molecules, have been widely studied in various types of cancers. ROS are considered to be normal byproducts of numerous cellular processes. Typically, cancer cells exhibit higher basal levels of ROS compared to normal cells as a result of an imbalance between oxidants and antioxidants. ROS have a dual role in cell metabolism: At low to moderate levels, ROS act as signal transducers to activate cell proliferation, migration, invasion and angiogenesis. In contrast, high levels of ROS cause damage to proteins, nucleic acids, lipids, membranes, and organelles, leading to cell death. Extensive studies have revealed that anticancer therapies that manipulate ROS levels, including immunotherapies, show promising in vitro as well as in vivo results. In this review, we summarize molecular mechanisms and oncogenic functions that modulate ROS levels and are useful for the development of cancer therapeutic strategies. This review also provides insights into the future development of effective agents that regulate the redox system for cancer treatment.
    Keywords:  Cell Death; Neoplasms; Oxidative Stress; Reactive Oxygen Species; Therapeutics
    DOI:  https://doi.org/10.1111/cas.15068
  16. J Hematol Oncol. 2021 Jul 22. 14(1): 114
    Metabolic landscapes in sarcomas.
    Richard Miallot, Franck Galland, Virginie Millet, Jean-Yves Blay, Philippe Naquet.
      Metabolic rewiring offers novel therapeutic opportunities in cancer. Until recently, there was scant information regarding soft tissue sarcomas, due to their heterogeneous tissue origin, histological definition and underlying genetic history. Novel large-scale genomic and metabolomics approaches are now helping stratify their physiopathology. In this review, we show how various genetic alterations skew activation pathways and orient metabolic rewiring in sarcomas. We provide an update on the contribution of newly described mechanisms of metabolic regulation. We underscore mechanisms that are relevant to sarcomagenesis or shared with other cancers. We then discuss how diverse metabolic landscapes condition the tumor microenvironment, anti-sarcoma immune responses and prognosis. Finally, we review current attempts to control sarcoma growth using metabolite-targeting drugs.
    Keywords:  Metabolism; Metabolite-targeted therapies; Metabolomics; Microenvironment; Sarcoma; Transcriptomics
    DOI:  https://doi.org/10.1186/s13045-021-01125-y
  17. ACS Chem Biol. 2021 Jul 23.
    Identification of a Small-Molecule Glucose Transporter Inhibitor, Glutipyran, That Inhibits Cancer Cell Growth.
    Makoto Kawatani, Harumi Aono, Sayoko Hiranuma, Takeshi Shimizu, Makoto Muroi, Naoko Ogawa, Tomokazu Ohishi, Shun-Ichi Ohba, Manabu Kawada, Toshihiko Nogawa, Akiko Okano, Daisuke Hashizume, Hiroyuki Osada.
      Cancer cells reprogram their metabolism to survive and grow. Small-molecule inhibitors targeting cancer are useful for studying its metabolic pathways and functions and for developing anticancer drugs. Here, we discovered that glutipyran and its derivatives inhibit glycolytic activity and cell growth in human pancreatic cancer cells. According to proteomic profiling of glutipyran-treated cells using our ChemProteoBase, glutipyran was clustered within the group of endoplasmic reticulum (ER) stress inducers that included glycolysis inhibitors. Glutipyran inhibited glucose uptake and suppressed the growth of various cancer cells, including A431 cells that express glucose transporter class I (GLUT1) and DLD-1 GLUT1 knockout cells. When cotreated with the mitochondrial respiration inhibitor metformin, glutipyran exhibited a synergistic antiproliferative effect. Metabolome analysis revealed that glutipyran markedly decreased most metabolites of the glycolytic pathway and the pentose phosphate pathway. Glutipyran significantly suppressed tumor growth in a xenograft mouse model of pancreatic cancer. These results suggest that glutipyran acts as a broad-spectrum GLUT inhibitor and reduces cancer cell growth.
    DOI:  https://doi.org/10.1021/acschembio.1c00480
  18. Transl Lung Cancer Res. 2021 Jun;10(6): 2523-2538
    One carbon metabolism in human lung cancer.
    Sha Yao, Luogen Peng, Omar Elakad, Stefan Küffer, Marc Hinterthaner, Bernhard C Danner, Alexander von Hammerstein-Equord, Philipp Ströbel, Hanibal Bohnenberger.
       Background: Lung cancer remains the major cause of cancer related death worldwide. The discovery of targeted therapies against activating mutations in genes like EGFR considerably improved the prognosis for a subgroup of patients but still leaves a large part without a targeted therapy. One carbon metabolism (1CM) has been investigated in several cancer entities and its increased activity has been linked to higher tumor aggressiveness and reduced prognosis. In spite of 1CM enzymes role and correlation to cancer cells progression, comprehensive analysis for the diagnostic and functional role of the complete 1CM enzymes in lung cancer has not been conducted so far.
    Methods: We investigated the prognostic and functional relevance of five major 1CM factors (MTHFD2, PGDH3, SHMT2, MTHFD1 and TYMS) in the three major subclasses of lung cancer [pulmonary adenocarcinoma (AC), squamous cell lung cancer (SQCLC) and small cell lung cancer (SCLC)]. We analyzed 1CM enzymes expression and clinicopathological correlation in patient derived tissue samples of 103 AC, 183 SQCLC and 37 SCLC patients by immunohistochemistry. Furthermore, the effect of 1CM enzymes expression on lung cancer cell proliferation and the response to chemotherapy was investigated in 15 representative AC, SQCLC and SCLC cell lines.
    Results: Expression of MTHFD2 and PGDH3 was significantly correlated to a worse overall survival only in AC patients. Cell proliferation assays resolved that all 1CM enzymes have a significant impact on cell growth in AC cell lines and are partially involved in cell proliferation in SQCLC and SCLC cell lines. In addition, expression of MTHFD2 correlated significantly with an increased pemetrexed chemoresistance.
    Conclusions: Expression of MTHFD2 significantly reduces the prognosis of AC patients. Furthermore, MTHFD2 expression is crucial for survival of AC cell lines and its expression correlates with resistance against Pemetrexed. As MTHFD2 is almost not expressed in healthy adult tissue, we therefore suggest that the inhibition of MTHFD2 might be a potential therapeutic strategy to surround pemetrexed resistance in AC.
    Keywords:  MTHFD2; One carbon metabolism (1CM); chemoresistance; lung cancer; pemetrexed
    DOI:  https://doi.org/10.21037/tlcr-20-1039
  19. Oncogene. 2021 Jul 21.
    AMPK-deficiency forces metformin-challenged cancer cells to switch from carbohydrate metabolism to ketogenesis to support energy metabolism.
    Flavio R Palma, Bianca A Ratti, Veronica Paviani, Diego R Coelho, Rodrigo Miguel, Jeanne M Danes, Sofia V Zaichik, Andre L de Abreu, Sueli O Silva, Yiliang Chen, Roy L Silverstein, Uppal Karan, Dean P Jones, Marcelo G Bonini.
      Epidemiologic studies in diabetic patients as well as research in model organisms have indicated the potential of metformin as a drug candidate for the treatment of various types of cancer, including breast cancer. To date most of the anti-cancer properties of metformin have, in large part, been attributed either to the inhibition of mitochondrial NADH oxidase complex (Complex I in the electron transport chain) or the activation of AMP-activated kinase (AMPK). However, it is becoming increasingly clear that AMPK activation may be critical to alleviate metabolic and energetic stresses associated with tumor progression suggesting that it may, in fact, attenuate the toxicity of metformin instead of promoting it. Here, we demonstrate that AMPK opposes the detrimental effects of mitochondrial complex I inhibition by enhancing glycolysis at the expense of, and in a manner dependent on, pyruvate availability. We also found that metformin forces cells to rewire their metabolic grid in a manner that depends on AMPK, with AMPK-competent cells upregulating glycolysis and AMPK-deficient cell resorting to ketogenesis. In fact, while the killing effects of metformin were largely rescued by pyruvate in AMPKcompetent cells, AMPK-deficient cells required instead acetoacetate, a product of fatty acid catabolism indicating a switch from sugar to fatty acid metabolism as a central resource for ATP production in these cells. In summary, our results indicate that AMPK activation is not responsible for metformin anticancer activity and may instead alleviate energetic stress by activating glycolysis.
    DOI:  https://doi.org/10.1038/s41388-021-01943-x
  20. Amino Acids. 2021 Jul 20.
    Proline dehydrogenase in cancer: apoptosis, autophagy, nutrient dependency and cancer therapy.
    Yating Liu, Chao Mao, Shuang Liu, Desheng Xiao, Ying Shi, Yongguang Tao.
      L-proline catabolism is emerging as a key pathway that is critical to cellular metabolism, growth, survival, and death. Proline dehydrogenase (PRODH) enzyme, which catalyzes the first step of proline catabolism, has diverse functional roles in regulating many pathophysiological processes, including apoptosis, autophagy, cell senescence, and cancer metastasis. Notably, accumulated evidence demonstrated that PRODH plays complex role in many types of cancers. In this review, we briefly introduce the function of PRODH, then its expression in different types of cancer. We next discuss the regulation of PRODH in cancer, the downstream pathways of PRODH and the therapies that are under investigation. Finally, we propose novel insights for future perspectives on the modulation of PRODH.
    Keywords:  Apoptosis; Autophagy; Cancer; L-proline; PRODH; p53
    DOI:  https://doi.org/10.1007/s00726-021-03032-5
  21. Bone Res. 2020 Jul 22. 8(1): 28
    An enhanced chemopreventive effect of methyl donor S-adenosylmethionine in combination with 25-hydroxyvitamin D in blocking mammary tumor growth and metastasis.
    Niaz Mahmood, Ani Arakelian, William J Muller, Moshe Szyf, Shafaat A Rabbani.
      Therapeutic targeting of metastatic breast cancer still remains a challenge as the tumor cells are highly heterogenous and exploit multiple pathways for their growth and metastatic spread that cannot always be targeted by a single-agent monotherapy regimen. Therefore, a rational approach through simultaneous targeting of several pathways may provide a better anti-cancer therapeutic effect. We tested this hypothesis using a combination of two nutraceutical agents S-adenosylmethionine (SAM) and Vitamin D (Vit. D) prohormone [25-hydroxyvitamin D; '25(OH)D'] that are individually known to exert distinct changes in the expression of genes involved in tumor growth and metastasis. Our results show that both SAM and 25(OH)D monotherapy significantly reduced proliferation and clonogenic survival of a panel of breast cancer cell lines in vitro and inhibited tumor growth, lung metastasis, and breast tumor cell colonization to the skeleton in vivo. However, these effects were significantly more pronounced in the combination setting. RNA-Sequencing revealed that the transcriptomic footprint on key cancer-related signaling pathways is broader in the combination setting than any of the monotherapies. Furthermore, comparison of the differentially expressed genes from our transcriptome analyses with publicly available cancer-related dataset demonstrated that the combination treatment upregulates genes from immune-related pathways that are otherwise downregulated in bone metastasis in vivo. Since SAM and Vit. D are both approved nutraceuticals with known safety profiles, this combination treatment may serve as a novel strategy to reduce breast cancer-associated morbidity and mortality.
    DOI:  https://doi.org/10.1038/s41413-020-0103-6
  22. Cancer Cell Int. 2021 Jul 20. 21(1): 386
    Tumor microenvironment: a prospective target of natural alkaloids for cancer treatment.
    Yanming Luo, Shuangshuang Yin, Jia Lu, Shiyue Zhou, Yingying Shao, Xiaomei Bao, Tao Wang, Yuling Qiu, Haiyang Yu.
      Malignant tumor has become one of the major diseases that seriously endangers human health. Numerous studies have demonstrated that tumor microenvironment (TME) is closely associated with patient prognosis. Tumor growth and progression are strongly dependent on its surrounding tumor microenvironment, because the optimal conditions originated from stromal elements are required for cancer cell proliferation, invasion, metastasis and drug resistance. The tumor microenvironment is an environment rich in immune/inflammatory cells and accompanied by a continuous, gradient of hypoxia and pH. Overcoming immunosuppressive environment and boosting anti-tumor immunity may be the key to the prevention and treatment of cancer. Most traditional Chinese medicine have been proved to have good anti-tumor activity, and they have the advantages of better therapeutic effect and few side effects in the treatment of malignant tumors. An increasing number of studies are giving evidence that alkaloids extracted from traditional Chinese medicine possess a significant anticancer efficiency via regulating a variety of tumor-related genes, pathways and other mechanisms. This paper reviews the anti-tumor effect of alkaloids targeting tumor microenvironment, and further reveals its anti-tumor mechanism through the effects of alkaloids on different components in tumor microenvironment.
    Keywords:  Alkaloids; Traditional Chinese Medicine; Tumor development; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12935-021-02085-6
  23. J Proteomics. 2021 Jul 20. pii: S1874-3919(21)00233-5. [Epub ahead of print] 104334
    SILAC-based quantitative MS approach reveals Withaferin A regulated proteins in prostate cancer.
    Ramesh Kumar, Debasis Nayak, Syam Prakash Somasekharan.
      Withaferin A (WA) is a steroidal lactone extracted from Withania somnifera, commonly known as Ashwagandha. WA has several therapeutic benefits. The current study aims to identify proteins that are potentially regulated by WA in prostate cancer (PCA) cells. We used a SILAC-based proteomic approach to analyze the expression of proteins in response to WA treatment at 4 h and 24 h time points in three PCA cell lines: 22Rv1, DU-145, and LNCaP. Ontology analysis suggested that prolonged treatment with WA upregulated the expression of proteins involved in stress-response pathways. Treatment with WA increased oxidative stress, reduced global mRNA translation, and elevated the expression of cytoprotective stress granule (SG) protein G3BP1. WA treatment also enhanced the formation of SGs. The elevated expression of G3BP1 and the formation of SGs might constitute a mechanism of cytoprotection in PCA cells. Knockdown of G3BP1 blocked SG formation and enhanced the efficacy of WA to reduce PCA cell survival. SIGNIFICANCE: Withaferin A, a steroidal lactone, extracted from Withania somniferum is a promising anti-cancer drug. Using a SILAC-based quantitative proteomic approach, we identified proteins changed by WA-treatment at 4 h and 24 h in three prostate cancer (PCA) cell lines. WA-treatment induced the expression of proteins involved in apoptosis and reduced the expression of proteins involved in cell growth at 4 h. WA-treatment for 24 h enhanced the expression of proteins involved in stress response pathways. WA-treated cells exhibited increased oxidative stress, reduced mRNA translation and enhanced SG formation. PCA is characterized by higher metabolic rate and increased oxidative stress. PCA with a higher stress tolerance can effectively adapt to anti-cancer treatment stress, leading to drug resistance and cellular protection. Enhancing the level of oxidative stress along with inhibition of corresponding cytoprotective stress response pathways is a feasible option to prevent PCA from getting adapted to treatment stress. WA-treatment induced oxidative stress, in combination with blocking SGs by G3BP1 targeting, offers a therapeutic strategy to reduce PCA cell survival.
    Keywords:  G3BP1; Natural compounds; Oxidative stress; Prostate cancer; Stress granule; Withaferin A
    DOI:  https://doi.org/10.1016/j.jprot.2021.104334
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