scholarly journals The Role of Succinic Acid Metabolism in Ovarian Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Lei Xia ◽  
Hairong Zhang ◽  
Xuezhen Wang ◽  
Xiaoyu Zhang ◽  
Ke Nie
Keyword(s):  
Ovarian Cancer ◽  
Succinic Acid ◽  
Tumor Therapy ◽  
Tca Cycle ◽  
Tumor Formation ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Metabolic Intermediate ◽  
Gynecological Malignancy

Ovarian cancer is one of the most common malignancies and the highest mortality among gynecological malignancy. The standard therapy options for patients with ovarian cancer are cytoreductive surgery and chemotherapy, and although most patients do better with standard treatment, it is easy to relapse and be resistant to chemotherapy. Therefore, it is important to find new therapeutic strategies. More recently, metabolic reprogramming has been recognized as a hallmark of cancer and has become a potential target for tumor therapy. Mutations of metabolic enzymes are closely related to the development of ovarian cancer. The metabolic reprogramming of ovarian cancer not only provides energy to tumor cells, but also participates in various biological processes as signaling molecules. Succinic acid (SA) is an important metabolic intermediate involved in a number of metabolic pathways, such as TCA cycle and glutamine metabolism, and is also widely present in a variety of plants and vegetables. Studies show abnormal SA metabolism in many tumors and affect tumor formation through a variety of mechanisms. But the role of SA in ovarian cancer is less studied. This paper reviews the role of SA and its abnormal metabolic pathway in ovarian cancer.

scholarly journals Lipid Metabolic Reprogramming in Hepatocellular Carcinoma

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 447 ◽  
Author(s):  
Hayato Nakagawa ◽  
Yuki Hayata ◽  
Satoshi Kawamura ◽  
Tomoharu Yamada ◽  
Naoto Fujiwara ◽  
...  
Keyword(s):  
Risk Factors ◽  
Hepatocellular Carcinoma ◽  
Local Environment ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Metabolic Alterations ◽  
Rich Condition ◽  
Visceral Adipose ◽  
Hcc Cells

Metabolic reprogramming for adaptation to the local environment has been recognized as a hallmark of cancer. Although alterations in fatty acid (FA) metabolism in cancer cells have received less attention compared to other metabolic alterations such as glucose or glutamine metabolism, recent studies have uncovered the importance of lipid metabolic reprogramming in carcinogenesis. Obesity and nonalcoholic steatohepatitis (NASH) are well-known risk factors of hepatocellular carcinoma (HCC), and individuals with these conditions exhibit an increased intake of dietary FAs accompanied by enhanced lipolysis of visceral adipose tissue due to insulin resistance, resulting in enormous exogenous FA supplies to hepatocytes via the portal vein and lymph vessels. This “lipid-rich condition” is highly characteristic of obesity- and NASH-driven HCC. Although the way in which HCC cells adapt to such a condition and exploit it to aid their progression is not understood, we recently obtained new insights into this mechanism through lipid metabolic reprogramming. In addition, accumulating evidence supports the importance of lipid metabolic reprogramming in various situations of hepatocarcinogenesis. Thus, in this review, we discuss the latest findings regarding the role of FA metabolism pathways in hepatocarcinogenesis, focusing on obesity- and NASH-driven lipid metabolic reprogramming.

scholarly journals A Critical Role of Glutamine and Asparagine γ-Nitrogen in Nucleotide Biosynthesis in Cancer Cells Hijacked by an Oncogenic Virus

mBio ◽  
2017 ◽  
Vol 8 (4) ◽  
Author(s):  
Ying Zhu ◽  
Tingting Li ◽  
Suzane Ramos da Silva ◽  
Jae-Jin Lee ◽  
Chun Lu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Cells ◽  
Metabolic Pathway ◽  
Tca Cycle ◽  
Glutamine Metabolism ◽  
Transformed Cells ◽  
Oncogenic Virus ◽  
Phosphoribosyl Pyrophosphate ◽  
Rate Limiting

ABSTRACT While glutamine is a nonessential amino acid that can be synthesized from glucose, some cancer cells primarily depend on glutamine for their growth, proliferation, and survival. Numerous types of cancer also depend on asparagine for cell proliferation. The underlying mechanisms of the glutamine and asparagine requirement in cancer cells in different contexts remain unclear. In this study, we show that the oncogenic virus Kaposi’s sarcoma-associated herpesvirus (KSHV) accelerates the glutamine metabolism of glucose-independent proliferation of cancer cells by upregulating the expression of numerous critical enzymes, including glutaminase 2 (GLS2), glutamate dehydrogenase 1 (GLUD1), and glutamic-oxaloacetic transaminase 2 (GOT2), to support cell proliferation. Surprisingly, cell crisis is rescued only completely by supplementation with asparagine but minimally by supplementation with α-ketoglutarate, aspartate, or glutamate upon glutamine deprivation, implying an essential role of γ-nitrogen in glutamine and asparagine for cell proliferation. Specifically, glutamine and asparagine provide the critical γ-nitrogen for purine and pyrimidine biosynthesis, as knockdown of four rate-limiting enzymes in the pathways, including carbamoylphosphate synthetase 2 (CAD), phosphoribosyl pyrophosphate amidotransferase (PPAT), and phosphoribosyl pyrophosphate synthetases 1 and 2 (PRPS1 and PRPS2, respectively), suppresses cell proliferation. These findings indicate that glutamine and asparagine are shunted to the biosynthesis of nucleotides and nonessential amino acids from the tricarboxylic acid (TCA) cycle to support the anabolic proliferation of KSHV-transformed cells. Our results illustrate a novel mechanism by which an oncogenic virus hijacks a metabolic pathway for cell proliferation and imply potential therapeutic applications in specific types of cancer that depend on this pathway. IMPORTANCE We have previously found that Kaposi’s sarcoma-associated herpesvirus (KSHV) can efficiently infect and transform primary mesenchymal stem cells; however, the metabolic pathways supporting the anabolic proliferation of KSHV-transformed cells remain unknown. Glutamine and asparagine are essential for supporting the growth, proliferation, and survival of some cancer cells. In this study, we have found that KSHV accelerates glutamine metabolism by upregulating numerous critical metabolic enzymes. Unlike most cancer cells that primarily utilize glutamine and asparagine to replenish the TCA cycle, KSHV-transformed cells depend on glutamine and asparagine for providing γ-nitrogen for purine and pyrimidine biosynthesis. We identified four rate-limiting enzymes in this pathway that are essential for the proliferation of KSHV-transformed cells. Our results demonstrate a novel mechanism by which an oncogenic virus hijacks a metabolic pathway for cell proliferation and imply potential therapeutic applications in specific types of cancer that depend on this pathway.

scholarly journals Spatially resolved metabolomics to discover tumor-associated metabolic alterations

2018 ◽  
Vol 116 (1) ◽  
pp. 52-57 ◽  
Author(s):  
Chenglong Sun ◽  
Tiegang Li ◽  
Xiaowei Song ◽  
Luojiao Huang ◽  
Qingce Zang ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Fatty Acid Biosynthesis ◽  
Spatial Information ◽  
Tumor Therapy ◽  
Metabolic Enzymes ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Ionization Mass ◽  
Metabolic Alterations ◽  
Spatially Resolved

Characterization of tumor metabolism with spatial information contributes to our understanding of complex cancer metabolic reprogramming, facilitating the discovery of potential metabolic vulnerabilities that might be targeted for tumor therapy. However, given the metabolic variability and flexibility of tumors, it is still challenging to characterize global metabolic alterations in heterogeneous cancer. Here, we propose a spatially resolved metabolomics approach to discover tumor-associated metabolites and metabolic enzymes directly in their native state. A variety of metabolites localized in different metabolic pathways were mapped by airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) in tissues from 256 esophageal cancer patients. In combination with in situ metabolomics analysis, this method provided clues into tumor-associated metabolic pathways, including proline biosynthesis, glutamine metabolism, uridine metabolism, histidine metabolism, fatty acid biosynthesis, and polyamine biosynthesis. Six abnormally expressed metabolic enzymes that are closely associated with the altered metabolic pathways were further discovered in esophageal squamous cell carcinoma (ESCC). Notably, pyrroline-5-carboxylate reductase 2 (PYCR2) and uridine phosphorylase 1 (UPase1) were found to be altered in ESCC. The spatially resolved metabolomics reveal what occurs in cancer at the molecular level, from metabolites to enzymes, and thus provide insights into the understanding of cancer metabolic reprogramming.

scholarly journals Increased expression of TET3 predicts unfavorable prognosis in patients with ovarian cancer-a bioinformatics integrative analysis

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Tiefeng Cao ◽  
Wenwei Pan ◽  
Xiaoli Sun ◽  
Huimin Shen
Keyword(s):  
Ovarian Cancer ◽  
Dna Demethylation ◽  
Integrative Analysis ◽  
Gynecological Malignancy ◽  
Kaplan Meier ◽  
The Family ◽  
Elevated Expression ◽  
Integrative Study ◽  
Cancer Tissues

Abstract Ovarian carcinoma is a lethal gynecological malignancy. Women with ovarian cancer (OC) are highly recurrent and typically diagnosed at late stage. Ten-eleven translocation protein 3 (TET3) belongs to the family of ten-eleven translocations (TETs) which induce DNA demethylation and gene regulation in epigenetic level by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Previous studies indicated that TET3 is overexpressed in ovarian cancer tissues. However, the clinic-pathological functions and prognostic values of TET3 remain unclear. Here we performed an integrative study to identify the role of TET3 by bioinformatics analysis. The TET3 expression in ovarian cancer was assessed with Oncomine database, and validated with TCGA and GTEx database. The correlation of TET3 gene alteration and clinic-pathological functions was addressed by integrative analysis of GEO datasets. Then we showed mainly TET3 gain and diploid but less deletion in ovarian cancer by copy number alteration (CNA) or mutation analysis with cBioPortal. Furthermore, by using Kaplan-Meier plotter (K-M plotter), we evaluated that high TET3 level was associated with poor survival in ovarian cancer patients, which was validated with analysis by PrognoScan database and gene differential analyses with TCGA and GTEx. This is the first study demonstrated that elevated expression of TET3 is associated with poor clinic-pathological functions, poor prognosis, wherein TET3, which presents epigenetic changes or methylation changes, might be served as a diagnostic marker or therapeutic target for ovarian cancer.

scholarly journals GLS-driven glutamine catabolism contributes to prostate cancer radiosensitivity by regulating the redox state, stemness and ATG5-mediated autophagy

2021 ◽  
Author(s):  
Anna Mukha ◽  
Ugur Kahya ◽  
Annett Linge ◽  
Oleg Chen ◽  
Steffen Lock ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Redox State ◽  
Cell Damage ◽  
Specific Antigen ◽  
Tumor Formation ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Blood Levels ◽  
Tumor Resistance ◽  
Prostate Cancer Stem Cells

Radiotherapy is one of the curative treatment options for localized prostate cancer (PCa). The curative potential of radiotherapy is mediated by irradiation-induced oxidative stress and DNA damage in tumor cells. However, PCa radiocurability can be impeded by tumor resistance mechanisms and normal tissue toxicity. Metabolic reprogramming is one of the major hallmarks of tumor progression and therapy resistance. Here, we found that radioresistant PCa cells and prostate cancer stem cells (CSCs) have a high glutamine demand. Glutaminase (GLS)-driven catabolism of glutamine serves not only for energy production but also for the maintenance of the redox state. Consequently, glutamine depletion or inhibition of critical regulators of glutamine utilization, such as glutaminase (GLS) and the transcription factor MYC results in PCa radiosensitization. On the contrary, we found that a combination of glutamine metabolism inhibitors with irradiation does not cause toxic effects on nonmalignant prostate cells. Glutamine catabolism contributes to the maintenance of CSCs through regulation of the alpha-ketoglutarate (α-KG)-dependent chromatin-modifying dioxygenase. The lack of glutamine results in the inhibition of CSCs with a high aldehyde dehydrogenase (ALDH) activity, decreases the frequency of the CSC populations in vivo and reduces tumor formation in xenograft mouse models. Moreover, this study shows that activation of the ATG5-mediated autophagy in response to a lack of glutamine is a tumor survival strategy to withstand radiation-mediated cell damage. In combination with autophagy inhibition, the blockade of glutamine metabolism might be a promising strategy for PCa radiosensitization. High blood levels of glutamine in PCa patients significantly correlate with a shorter prostate-specific antigen (PSA) doubling time. Furthermore, high expression of critical regulators of glutamine metabolism, GLS1 and MYC, is significantly associated with a decreased progression-free survival in PCa patients treated with radiotherapy. Our findings demonstrate that GLS-driven glutaminolysis is a prognostic biomarker and therapeutic target for PCa radiosensitization.

scholarly journals Emergence of MicroRNAs as Key Players in Cancer Cell Metabolism

2019 ◽  
Vol 65 (9) ◽  
pp. 1090-1101 ◽  
Author(s):  
Sugarniya Subramaniam ◽  
Varinder Jeet ◽  
Judith A Clements ◽  
Jennifer H Gunter ◽  
Jyotsna Batra
Keyword(s):  
Fatty Acid ◽  
Signaling Pathways ◽  
Tumor Cells ◽  
Metabolic Pathways ◽  
Acid Metabolism ◽  
Tca Cycle ◽  
Metabolic Reprogramming ◽  
Metabolic Adaptation ◽  
Novel Therapeutic

AbstractBACKGROUNDMetabolic reprogramming is a hallmark of cancer. MicroRNAs (miRNAs) have been found to regulate cancer metabolism by regulating genes involved in metabolic pathways. Understanding this layer of complexity could lead to the development of novel therapeutic approaches.CONTENTmiRNAs are noncoding RNAs that have been implicated as master regulators of gene expression. Studies have revealed the role of miRNAs in the metabolic reprogramming of tumor cells, with several miRNAs both positively and negatively regulating multiple metabolic genes. The tricarboxylic acid (TCA) cycle, aerobic glycolysis, de novo fatty acid synthesis, and altered autophagy allow tumor cells to survive under adverse conditions. In addition, major signaling molecules, hypoxia-inducible factor, phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin/phosphatase and tensin homolog, and insulin signaling pathways facilitate metabolic adaptation in tumor cells and are all regulated by miRNAs. Accumulating evidence suggests that miRNA mimics or inhibitors could be used to modulate the activity of miRNAs that drive tumor progression via altering their metabolism. Currently, several clinical trials investigating the role of miRNA-based therapy for cancer have been launched that may lead to novel therapeutic interventions in the future.SUMMARYIn this review, we summarize cancer-related metabolic pathways, including glycolysis, TCA cycle, pentose phosphate pathway, fatty acid metabolism, amino acid metabolism, and other metabolism-related oncogenic signaling pathways, and their regulation by miRNAs that are known to lead to tumorigenesis. Further, we discuss the current state of miRNA therapeutics in the clinic and their future potential.

scholarly journals Special Agents Hunting Down Women Silent Killer: The Emerging Role of the p38αKinase

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Valentina Grossi ◽  
Cristiano Simone
Keyword(s):  
Ovarian Cancer ◽  
Drug Resistance ◽  
Metabolic Reprogramming ◽  
Proliferating Cells ◽  
Improve Patient Survival ◽  
High Incidence ◽  
Current Therapies ◽  
Therapy Success ◽  
Improve Patient

Ovarian cancer is sensitive to chemotherapy with platinum compounds; however, the therapy success rate is significantly lowered by a high incidence of recurrence and by the acquisition of drug resistance. These negative outcomes mainly depend on altered apoptotic and drug resistance pathways, determining the need for the design of new therapeutic strategies to improve patient survival. This challenge has become even more critical because it has been recognized that hindering uncontrolled cell growth is not sufficient as the only curative approach. In fact, while current therapies are mostly conceived to impair survival of highly proliferating cells, several lines of research are now focusing on cancer-specific features to specifically target malignant cells with the aim of avoiding drug resistance and reducing adverse effects. Recently, great interest has been generated by the identification of metabolic reprogramming mechanisms occurring in cancer cells, such as the increase in glycolysis levels. In this light, pharmacologic manipulation of relevant pathways involved in cancer-specific metabolism and drug resistance could prove an effective approach to treat ovarian cancer patients.

scholarly journals Lipid Metabolism in Oncology: Why It Matters, How to Research, and How to Treat

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 474
Author(s):  
Yuki Matsushita ◽  
Hayato Nakagawa ◽  
Kazuhiko Koike
Keyword(s):  
Lipid Metabolism ◽  
Cancer Biology ◽  
Cellular Level ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Cellular Functions ◽  
Altered Lipid Metabolism ◽  
Altered Lipid

Lipids in our body, which are mainly composed of fatty acids, triacylglycerides, sphingolipids, phospholipids, and cholesterol, play important roles at the cellular level. In addition to being energy sources and structural components of biological membranes, several types of lipids serve as signaling molecules or secondary messengers. Metabolic reprogramming has been recognized as a hallmark of cancer, but changes in lipid metabolism in cancer have received less attention compared to glucose or glutamine metabolism. However, recent innovations in mass spectrometry- and chromatography-based lipidomics technologies have increased our understanding of the role of lipids in cancer. Changes in lipid metabolism, so-called “lipid metabolic reprogramming”, can affect cellular functions including the cell cycle, proliferation, growth, and differentiation, leading to carcinogenesis. Moreover, interactions between cancer cells and adjacent immune cells through altered lipid metabolism are known to support tumor growth and progression. Characterization of cancer-specific lipid metabolism can be used to identify novel metabolic targets for cancer treatment, and indeed, several clinical trials are currently underway. Thus, we discuss the latest findings on the roles of lipid metabolism in cancer biology and introduce current advances in lipidomics technologies, focusing on their applications in cancer research.

scholarly journals Silencing PTEN in the fallopian tube promotes enrichment of cancer stem cell-like function through loss of PAX2

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Angela Russo ◽  
Jose A. Colina ◽  
Junlone Moy ◽  
Seth Baligod ◽  
Austin A. Czarnecki ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Fallopian Tube ◽  
Cell Function ◽  
Tumor Formation ◽  
Stem Cell Markers ◽  
Gynecological Malignancy ◽  
Cancer Stem Cell Markers ◽  
Cancer Tumor

AbstractHigh-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy that is primarily detected at the metastatic stage. Most HGSOC originates from the fallopian tube epithelium (FTE) and metastasizes to the ovary before invading the peritoneum; therefore, it is crucial to study disease initiation and progression using FTE-derived models. We previously demonstrated that loss of PTEN from the FTE leads to ovarian cancer. In the present study, loss of PTEN in FTE led to the enrichment of cancer stem cell markers such as LGR5, WNT4, ALDH1, CD44. Interestingly, loss of the transcription factor PAX2, which is a common and early alteration in HGSOC, played a pivotal role in the expression of cancer stem-like cells (CSC) markers and cell function. In addition, loss of PTEN led to the generation of two distinct subpopulations of cells with different CSC marker expression, tumorigenicity, and chemoresistance profiles. Taken together, these data suggest that loss of PTEN induces reprogramming of the FTE cells into a more stem-like phenotype due to loss of PAX2 and provides a model to study early events during the FTE-driven ovarian cancer tumor formation.

scholarly journals SARS-CoV-2 and Glutamine: SARS-CoV-2 Triggered Pathogenesis via Metabolic Reprograming of Glutamine in Host Cells

2021 ◽  
Vol 7 ◽  
Author(s):  
Shiv Bharadwaj ◽  
Mahendra Singh ◽  
Nikhil Kirtipal ◽  
Sang Gu Kang
Keyword(s):  
Cancer Metabolism ◽  
Viral Infections ◽  
Mammalian Target Of Rapamycin ◽  
Metabolic Reprogramming ◽  
Host Cells ◽  
Glutamine Metabolism ◽  
Altered Glucose

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as coronavirus disease 2019 (COVID-19) pandemic, has killed more than a million people worldwide, and researchers are constantly working to develop therapeutics in the treatment and prevention of this new viral infection. To infect and induced pathogenesis as observed in other viral infections, we postulated that SARS-CoV-2 may also require an escalation in the anabolic metabolism, such as glucose and glutamine, to support its energy and biosynthetic requirements during the infection cycle. Recently, the requirement of altered glucose metabolism in SARS-CoV-2 pathogenesis was demonstrated, but the role of dysregulated glutamine metabolism is not yet mentioned for its infection. In this perspective, we have attempted to provide a summary of possible biochemical events on putative metabolic reprograming of glutamine in host cells upon SARS-CoV-2 infection by comparison to other viral infections/cancer metabolism and available clinical data or research on SARS-CoV-2 pathogenesis. This systematic hypothesis concluded the vital role of glutaminase-1 (GLS1), phosphoserine aminotransferase (PSAT1), hypoxia-inducible factor-1 alpha (HIF-1α), mammalian target of rapamycin complex 1 (mTORC1), glutamine-fructose amidotransferase 1/2 (GFAT1/2), and transcription factor Myc as key cellular factors to mediate and promote the glutamine metabolic reprogramming in SARS-CoV-2 infected cells. In absence of concrete data available for SARS-CoV-2 induced metabolic reprogramming of glutamine, this study efforts to connect the gaps with available clinical shreds of evidence in SARS-CoV-2 infection with altered glutamine metabolism and hopefully could be beneficial in the designing of strategic methods for therapeutic development with elucidation using in vitro or in vivo approaches.

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