bims-glucam 2021-06-20 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2021–06–20
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Ovarian Cancer modulates the immunosuppressive function of CD11b+Gr1+ myeloid cells via glutamine metabolism.
Glutamine addiction in virus-infected mammalian cells: A target of the innate immune system?
GLS1 depletion inhibited colorectal cancer proliferation and migration via redox/Nrf2/autophagy-dependent pathway.
VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway.
Metabolic reprogramming due to hypoxia in pancreatic cancer: Implications for tumor formation, immunity, and more.
Overcoming chemoresistance by targeting reprogrammed metabolism: the Achilles' heel of pancreatic ductal adenocarcinoma.
Glutamine regulates ovarian cancer cell migration and invasion through ETS1.
Ketogenic Metabolic Therapy, Without Chemo or Radiation, for the Long-Term Management of IDH1-Mutant Glioblastoma: An 80-Month Follow-Up Case Report.
Autophagy Regulates Stress Responses, Metabolism, and Anticancer Immunity.
Colorectal cancer cells utilize autophagy to maintain mitochondrial metabolism for cell proliferation under nutrient stress.
Memantine shifts cancer cell metabolism via AMPK1/2 mediated energetic switch in A549 lung cancer cells.
Targeting nucleotide metabolism as the nexus of viral infections, cancer, and the immune response.
NADK is activated by oncogenic signaling to sustain pancreatic ductal adenocarcinoma.
mTOR-Rictor-EGFR axis in oncogenesis and diagnosis of glioblastoma multiforme.
Metabolic Phenotypes, Dependencies, and Adaptation in Lung Cancer.
A ratiometric fluorescent probe for real-time monitoring of intracellular glutathione fluctuations in response to cisplatin.
Glucose regulates expression of pro-inflammatory genes IL-1β and IL-12 through a mechanism involving hexosamine biosynthesis pathway dependent regulation of αEcatenin.

Mol Metab. 2021 Jun 15. pii: S2212-8778(21)00117-4. [Epub ahead of print] 101272

Ovarian Cancer modulates the immunosuppressive function of CD11b+Gr1+ myeloid cells via glutamine metabolism.

Mary Priyanka Udumula, Sharif Sakr, Sajad Dar, Ayesha B Alvero, Rouba Ali-Fehmi, Eman Abdulfatah, Jing Li, Jun Jiang, Amy Tang, Thomas Buekers, Robert Morris, Adnan Munkarah, Shailendra Giri, Ramandeep Rattan.

   OBJECTIVE: Immature CD11b+Gr1+ myeloid cells that acquire immunosuppressive capability, also known as myeloid-derived suppressor cells (MDSCs), are a heterogeneous population of cells that regulate immune responses. Our study's objective was to elucidate the role of ovarian cancer microenvironment in regulating the immunosuppressive function of CD11b+Gr1+ myeloid cells.
METHODS: All studies were performed using the intraperitoneal ID8 syngeneic epithelial ovarian cancer mouse model. Myeloid cell depletion and immunotherapy were carried out using anti-Gr1 mAb, gemcitabine treatments, and/or anti PD1 mAb. The treatment effect was assessed by survival curve, in situ luciferase-guided imaging, and histopathologic evaluation. Adoptive transfer assays were carried out between congenic CD45.2 and CD45.1 mice. Immune surface and intracellular markers were assessed by flow cytometry. ELISA, western blot, and RT-PCR techniques were employed to assess protein and RNA expression of various markers. Bone marrow-derived myeloid cells were used for ex-vivo studies.
RESULTS: Depletion of Gr1+ immunosuppressive myeloid cells alone and in combination with anti-PD1 immunotherapy inhibited ovarian cancer growth. These findings, in addition to the adoptive transfer studies, validated the role of immunosuppressive CD11b+Gr1+ myeloid cells in promoting ovarian cancer. Mechanistic investigations showed that ID8 tumor cells and their microenvironment produced both recruitment and regulatory factors for immunosuppressive CD11b+Gr1+ myeloid cells. CD11b+Gr1+ myeloid cells primed by ID8 tumors showed increased immunosuppressive marker expression and acquired an energetic metabolic phenotype promoted mainly by increased oxidative phosphorylation fueled by glutamine. Inhibiting the glutamine metabolic pathway reduced the increased oxidative phosphorylation and decreased immunosuppressive markers expression and function. Dihydrolipoamide succinyl transferase (DLST), a subunit of α-KGDC in the TCA cycle, was found be the most significantly elevated gene in tumor primed myeloid cells. Inhibition of DLST reduced oxidative phosphorylation, immunosuppressive marker expression, and function in myeloid cells.
CONCLUSION: Our study shows that the ovarian cancer microenvironment can regulate the metabolism and function of immunosuppressive CD11b+Gr1+ myeloid cells and modulate its immune microenvironment. Targeting glutamine metabolism via DLST in those immunosuppressive myeloid decreased their activity, leading to a reduction in the immunosuppressive tumor microenvironment. Thus, targeting glutamine metabolism has the potential to enhance the success of immunotherapy in ovarian cancer.

Keywords:  CD11b(+)Gr1(+) immunosuppressive cells; DLST; MDSCs; glutamine metabolism; ovarian cancer; α-KDHC

DOI:  https://doi.org/10.1016/j.molmet.2021.101272
Med Hypotheses. 2021 Jun 02. pii: S0306-9877(21)00139-0. [Epub ahead of print]153 110620

Glutamine addiction in virus-infected mammalian cells: A target of the innate immune system?

C Koufaris, V Nicolaidou.

  Control of core cell metabolism is a key aspect of the evolutionary conflict between viruses and the host's defence mechanisms. From their side, the invading viruses press the accelerator on their host cell's glycolysis, fatty acid, and glutaminolytic metabolic processes among others. It is also well established that activation of innate immune system responses modulates facets of metabolism such as that of polyamine, cholesterol, tryptophan and many more. But what about glutamine, a proteogenic amino acid that is a crucial nutrient for multiple cellular biosynthetic processes? Although mammalian cells can normally synthesize glutamine de novo, it has been noted that infections with genetically and phylogenetically diverse viruses are followed by the acquisition of a dependency on supplies of exogenous glutamine i.e. "glutamine addiction". Here we present our novel hypothesis that glutamine metabolism is also a target of the innate immune system, possibly through the action of interferons, as part of the evolutionary conserved antiviral metabolic reprogramming.

Keywords:  Cellular metabolism; Glutamine; Immune response; Viral infection

DOI:  https://doi.org/10.1016/j.mehy.2021.110620
Arch Biochem Biophys. 2021 Jun 11. pii: S0003-9861(21)00213-7. [Epub ahead of print]708 108964

GLS1 depletion inhibited colorectal cancer proliferation and migration via redox/Nrf2/autophagy-dependent pathway.

Hui-Yun Liu, Hong-Sheng Zhang, Min-Yao Liu, Hong-Ming Li, Xin-Yu Wang, Miao Wang.

  Cancer cells can metabolize glutamine to replenish TCA cycle intermediates for cell survival. Glutaminase (GLS1) is over-expressed in multiple cancers, including colorectal cancer (CRC). However, the role of GLS1 in colorectal cancer development has not yet fully elucidated. In this study, we found that GLS1 levels were significantly increased in CRC cells. Knockdown of GLS1 by shRNAs as well as GLS1 inhibitor BPTES decreased DLD1 and SW480 cell proliferation, colony formation and migration. Knockdown of GLS1 as well as BPTES induced reactive oxygen species (ROS) production, down-regulation of GSH/GSSG ratio, an decrease in Nrf2 protein expression and an increase in cytoplasmic Nrf2 protein expression in DLD1 and SW480 cells. Furthermore, Knockdown of GLS1 as well as BPTES inhibited autophagy pathway, antioxidant NAC and Nrf2 activator could reversed inhibition of GLS1-mediated an decrease in autophagic flux in DLD1 and SW480 cells. Depletion of GLS1-induced inhibition of DLD1 and SW480 CRC cell proliferation, colony formation and migration was reversed by autophagy inducer rapamycin. These results suggest that targeting GLS1 might be a new potential therapeutic target for the treatment of CRC.

Keywords:  Autophagy; Colorectal cancer; GLS1; Redox

DOI:  https://doi.org/10.1016/j.abb.2021.108964
Cell Death Dis. 2021 Jun 16. 12(7): 621

VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway.

Ying Tong, Jinyan Kai, Shuo Wang, Yiwen Yu, Suhong Xie, Hui Zheng, Yanchun Wang, Yixuan Liu, Keyu Zhu, Xiaolin Guan, Lin Guo, Renquan Lu.

Clear cell renal cell carcinomas (ccRCC) reprogram carbon metabolism responses to hypoxia, thereby promoting utilization of glutamine. Recently, sirtuin 4 (SIRT4), a novel molecular has turned out to be related to alternating glutamine metabolism and modulating the tumor microenvironment. However, the role of SIRT4 in ccRCC remains poorly understood. Here, we illustrated that the expression of SIRT4 is markedly reduced in cancerous tissues, and closely associated with malignancy stage, grade, and prognosis. In ccRCC cells, SIRT4 exerted its proapoptotic activity through enhancing intracellular reactive oxygen species (ROS). Heme oxygenase-1 (HO-1) is part of an endogenous defense system against oxidative stress. Nevertheless, overexpression of SIRT4 hindered the upregulation of HO-1 in von Hippel-Lindau (VHL)-proficient cells and repressed its expression in VHL-deficient cells. This discrepancy indicated that competent VHL withstands the inhibitory role of SIRT4 on HIF-1α/HO-1. Functionally, overexpression of HO-1 counteracted the promotional effects of SIRT4 on ROS accumulation and apoptosis. Mechanistically, SIRT4 modulates ROS and HO-1 expression via accommodating p38-MAPK phosphorylation. By contrast, downregulation of p38-MAPK by SB203580 decreased intracellular ROS level and enhanced the expression of HO-1. Collectively, this work revealed a potential role for SIRT4 in the stimulation of ROS and the modulation of apoptosis. SIRT4/HO-1 may act as a potential therapeutic target, especially in VHL-deficient ccRCCs.

DOI: https://doi.org/10.1038/s41419-021-03901-7
Biomed Pharmacother. 2021 Jun 10. pii: S0753-3322(21)00580-1. [Epub ahead of print]141 111798

Metabolic reprogramming due to hypoxia in pancreatic cancer: Implications for tumor formation, immunity, and more.

Xiadong Hao, Yidan Ren, Maoxiao Feng, Qin Wang, Yunshan Wang.

  Hypoxia is a common phenomenon in most malignant tumors, especially in pancreatic cancer (PC). Hypoxia is the result of unlimited tumor growth and plays an active role in promoting tumor survival, progression, and invasion. As the part of the hypoxia microenvironment in PC is gradually clarified, hypoxia is becoming a key determinant and an important therapeutic target of pancreatic cancer. To adapt to the severe hypoxia environment, cells have changed their metabolic phenotypes to maintain their survival and proliferation. Enhanced glycolysis is the most prominent feature of cancer cells' metabolic reprogramming in response to hypoxia. It provides the energy source for hypoxic cancer cells (although it provides less than oxidative phosphorylation) and produces metabolites that can be absorbed and utilized by normoxic cancer cells. In addition, the uptake of glutamine and fatty acids by hypoxic cancer cells is also increased, which is also conducive to tumor progression. Their metabolites are pooled in the hexosamine biosynthesis pathway (HBP). As a nutrition sensor, HBP, in turn, can coordinate glucose and glutamine metabolism. Its end product, UDP-GlcNAc, is the substrate of protein post-translational modification (PTM) involved in various signaling pathways supporting tumor progression. Adaptive metabolic changes of cancer cells promote their survival and affect tumor immune cells in the tumor microenvironment (TME), which contributes to tumor immunosuppressive microenvironment and induces tumor immunotherapy resistance. Here, we summarize the hypoxic microenvironment, its effect on metabolic reprogramming, and its contribution to immunotherapy resistance in pancreatic cancer.

Keywords:  Hypoxia; Immunosuppressive microenvironment; Metabolic reprogramming; Pancreatic cancer (PC)

DOI:  https://doi.org/10.1016/j.biopha.2021.111798
Cell Mol Life Sci. 2021 Jun 15.

Overcoming chemoresistance by targeting reprogrammed metabolism: the Achilles' heel of pancreatic ductal adenocarcinoma.

Abudureyimu Tuerhong, Jin Xu, Si Shi, Zhen Tan, Qingcai Meng, Jie Hua, Jiang Liu, Bo Zhang, Wei Wang, Xianjun Yu, Chen Liang.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death due to its late diagnosis that removes the opportunity for surgery and metabolic plasticity that leads to resistance to chemotherapy. Metabolic reprogramming related to glucose, lipid, and amino acid metabolism in PDAC not only enables the cancer to thrive and survive under hypovascular, nutrient-poor and hypoxic microenvironments, but also confers chemoresistance, which contributes to the poor prognosis of PDAC. In this review, we systematically elucidate the mechanism of chemotherapy resistance and the relationship of metabolic programming features with resistance to anticancer drugs in PDAC. Targeting the critical enzymes and/or transporters involved in glucose, lipid, and amino acid metabolism may be a promising approach to overcome chemoresistance in PDAC. Consequently, regulating metabolism could be used as a strategy against PDAC and could improve the prognosis of PDAC.

Keywords:  Chemotherapy; Glutamine; Glycolysis; Lipogenesis; Pancreatic cancer

DOI:  https://doi.org/10.1007/s00018-021-03866-y
Heliyon. 2021 May;7(5): e07064

Glutamine regulates ovarian cancer cell migration and invasion through ETS1.

Parash Prasad, Sib Sankar Roy.

  Cancer cells are dependent on glutamine for their metabolism and growth. Despite being the most abundant amino acid in the blood, glutamine deprivation occurs in the core of the tumor rendering less access to glutamine to the nearby tumor cells. Tumor cells mostly use the glutamine for mitochondrial oxidative phosphorylation (OXPHOS) to produce energy and the ingredients of the biomass required for the highly proliferating and metastatic ovarian cancer cells. But there is a lack of reports on the regulation of glutamine starvation on metastatic behavior and epithelial to mesenchymal transition (EMT) of ovarian cancer cells. We found that glutamine starvation reduced the migration and invasion properties of the ovarian cancer cells, PA1 and SKOV3. The expression of the invasion-inducing proteins, like matrix metalloproteinases (MMP2 and MMP9), were downregulated upon glutamine starvation. MMP genes are mostly regulated by the ETS1 oncogenic transcription factor in invasive tumor cells. Here we demonstrated the significant involvement of ETS1 on EMT and invasion in glutamine-deprived cells. We have further shown that the regulation of ETS1 expression and nuclear localization upon glutamine starvation is controlled in a cell type-specific manner. In PA1 cells, glutamine-induced ETS1 over-expression is HIF1α-dependent, while in SKOV3, its translocation to the nucleus is regulated through the mTOR pathway. Considering all, our study suggests that glutamine plays a very significant role in migration and invasion in ovarian cancer cells and ETS1 plays a key role in inducing such oncogenic parameters.

Keywords:  ETS1; Glutamine; MMP

DOI:  https://doi.org/10.1016/j.heliyon.2021.e07064
Front Nutr. 2021 ;8 682243

Ketogenic Metabolic Therapy, Without Chemo or Radiation, for the Long-Term Management of IDH1-Mutant Glioblastoma: An 80-Month Follow-Up Case Report.

Thomas N Seyfried, Aditya G Shivane, Miriam Kalamian, Joseph C Maroon, Purna Mukherjee, Giulio Zuccoli.

  Background: Successful treatment of glioblastoma (GBM) remains futile despite decades of intense research. GBM is similar to most other malignant cancers in requiring glucose and glutamine for growth, regardless of histological or genetic heterogeneity. Ketogenic metabolic therapy (KMT) is a non-toxic nutritional intervention for cancer management. We report the case of a 32-year-old man who presented in 2014 with seizures and a right frontal lobe tumor on MRI. The tumor cells were immunoreactive with antibodies to the IDH1 (R132H) mutation, P53 (patchy), MIB-1 index (4-6%), and absent ATRX protein expression. DNA analysis showed no evidence of methylation of the MGMT gene promoter. The presence of prominent microvascular proliferation and areas of necrosis were consistent with an IDH-mutant glioblastoma (WHO Grade 4). Methods: The patient refused standard of care (SOC) and steroid medication after initial diagnosis, but was knowledgeable and self-motivated enough to consume a low-carbohydrate ketogenic diet consisting mostly of saturated fats, minimal vegetables, and a variety of meats. The patient used the glucose ketone index calculator to maintain his Glucose Ketone Index (GKI) near 2.0 without body weight loss. Results: The tumor continued to grow slowly without expected vasogenic edema until 2017, when the patient opted for surgical debulking. The enhancing area, centered in the inferior frontal gyrus, was surgically excised. The pathology specimen confirmed IDH1-mutant GBM. Following surgery, the patient continued with a self-administered ketogenic diet to maintain low GKI values, indicative of therapeutic ketosis. At the time of this report (May 2021), the patient remains alive with a good quality of life, except for occasional seizures. MRI continues to show slow interval progression of the tumor. Conclusion: This is the first report of confirmed IDH1-mutant GBM treated with KMT and surgical debulking without chemo- or radiotherapy. The long-term survival of this patient, now at 80 months, could be due in part to a therapeutic metabolic synergy between KMT and the IDH1 mutation that simultaneously target the glycolysis and glutaminolysis pathways that are essential for GBM growth. Further studies are needed to determine if this non-toxic therapeutic strategy could be effective in providing long-term management for other GBM patients with or without IDH mutations.

Keywords:  2-hydroxyglutarate; carnivore diet; fasting; glutaminolysis; glycolysis; mitochondrial substrate level phosphorylation (mSLP); standard of care

DOI:  https://doi.org/10.3389/fnut.2021.682243
Trends Cancer. 2021 Jun 07. pii: S2405-8033(21)00104-7. [Epub ahead of print]

Autophagy Regulates Stress Responses, Metabolism, and Anticancer Immunity.

Eileen White, Edmund C Lattime, Jessie Yanxiang Guo.

  Autophagy is a catabolic intracellular nutrient-scavenging pathway triggered by nutrient deprivation and stress that captures and degrades intracellular proteins and organelles in lysosomes. The breakdown products are then recycled into metabolic pathways to sustain survival. Organelle turnover by autophagy contributes to quality control and suppresses inflammation. Autophagy is upregulated in many cancers and supports their growth, survival, and malignancy in a tumor cell-autonomous fashion. Host autophagy also promotes tumor growth by maintaining a supply of essential nutrients and suppressing innate and adaptive antitumor immune responses. Autophagy is also upregulated in response to cancer therapy and confers treatment resistance. Thus, autophagy is a cancer vulnerability and its inhibition is under investigation as a novel therapeutic approach.

Keywords:  T cells; autophagy; cancer; immune response; interferon; metabolism

DOI:  https://doi.org/10.1016/j.trecan.2021.05.003
JCI Insight. 2021 Jun 17. pii: 138835. [Epub ahead of print]

Colorectal cancer cells utilize autophagy to maintain mitochondrial metabolism for cell proliferation under nutrient stress.

Samantha N Devenport, Rashi Singhal, Megan D Radyk, Joseph G Taranto, Samuel A Kerk, Brandon Chen, Joshua W Goyert, Chesta Jain, Nupur K Das, Katherine Oravecz-Wilson, Li Zhang, Joel K Greenson, Y Eugene Chen, Scott A Soleimanpour, Pavan Reddy, Costas A Lyssiotis, Yatrik M Shah.

  Cancer cells re-program cellular metabolism to maintain adequate nutrient pools to sustain proliferation. Moreover, autophagy is a regulated mechanism to breakdown dysfunctional cellular components and recycle cellular nutrients. However, the requirement for autophagy and the integration in cancer cell metabolism is not clear in colon cancer. Here we show a cell-autonomous dependency of autophagy for cell growth in colorectal cancer. Loss of epithelial autophagy inhibits tumor growth in both sporadic and colitis associated cancer models. Genetic and pharmacological inhibition of autophagy inhibits cell growth in colon cancer-derived cell lines and patient-derived enteroid models. Importantly, normal colon epithelium and patient-derived normal enteroid growth was not decreased following autophagy inhibition. To couple the role of autophagy to cellular metabolism, a cell culture screen in conjunction with metabolomic analysis was performed. We identified a critical role of autophagy to maintain mitochondrial metabolites for growth. Loss of mitochondrial recycling through inhibition of mitophagy hinders colon cancer cell growth. These findings have revealed a cell-autonomous role of autophagy that plays a critical role in regulating nutrient pools in vivo and in cell models and provides therapeutic targets for colon cancer.

Keywords:  Colorectal cancer; Gastroenterology; Oncology

DOI:  https://doi.org/10.1172/jci.insight.138835
EXCLI J. 2021 ;20 223-231

Memantine shifts cancer cell metabolism via AMPK1/2 mediated energetic switch in A549 lung cancer cells.

Gulsah Albayrak, Funda Demirtas Korkmaz.

  Memantine is used to prevent glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease. As glutamine is one of the major source of anabolism in fast growing cancer cells, we aimed to interfere with the cancer cell metabolism in A549 lung cancer cells by using memantine. The effects of memantine on cell cycle progression and cell death in A549 cells were assessed by MTT assay and PI staining. Cells were treated with 0.25 mM memantine for 48 hours and then cell metabolism (AMPKA1, AMPKA2, HIF1A, B-catenin, PKM), apoptosis (p53, p21, Bax, Bcl-XL, NOXA, PUMA) and autophagy related (LC3B-I, LC3B-II, SQSTM1) mRNA and protein expressions were investigated by RT-qPCR and western blotting. Memantine decreased cell viability significantly in a concentration-dependent manner by inducing G0/G1 cell cycle arrest. Our results suggest that memantine activates AMPK1/2 significantly (p=0.039 and p=0.0105) that led cells through apoptosis and autophagy by decreasing cancer cell metabolism regulators like HIF1A, B-catenin and PKM as the consequence of this energetic shift. Memantine represents a useful tool to target metabolism in cancer cells. Therefore, it might be used a new repurposed drug in cancer treatment.

Keywords:  cancer cell metabolism; drug re-purposing; lung cancer; memantine

DOI:  https://doi.org/10.17179/excli2020-2890
Sci Adv. 2021 May;pii: eabg6165. [Epub ahead of print]7(21):

Targeting nucleotide metabolism as the nexus of viral infections, cancer, and the immune response.

Yarden Ariav, James H Ch'ng, Heather R Christofk, Noga Ron-Harel, Ayelet Erez.

Virus-infected cells and cancers share metabolic commonalities that stem from their insatiable need to replicate while evading the host immune system. These similarities include hijacking signaling mechanisms that induce metabolic rewiring in the host to up-regulate nucleotide metabolism and, in parallel, suppress the immune response. In both cancer and viral infections, the host immune cells and, specifically, lymphocytes augment nucleotide synthesis to support their own proliferation and effector functions. Consequently, established treatment modalities targeting nucleotide metabolism against cancers and virally infected cells may result in restricted immune response. Encouragingly, following the introduction of immunotherapy against cancers, multiple studies improved our understanding for improving antigen presentation to the immune system. We propose here that understanding the immune consequences of targeting nucleotide metabolism against cancers may be harnessed to optimize therapy against viral infections.

DOI: https://doi.org/10.1126/sciadv.abg6165
Cell Rep. 2021 Jun 15. pii: S2211-1247(21)00597-0. [Epub ahead of print]35(11): 109238

NADK is activated by oncogenic signaling to sustain pancreatic ductal adenocarcinoma.

Tanya Schild, Melanie R McReynolds, Christie Shea, Vivien Low, Bethany E Schaffer, John M Asara, Elena Piskounova, Noah Dephoure, Joshua D Rabinowitz, Ana P Gomes, John Blenis.

  Metabolic adaptations and the signaling events that control them promote the survival of pancreatic ductal adenocarcinoma (PDAC) at the fibrotic tumor site, overcoming stresses associated with nutrient and oxygen deprivation. Recently, rewiring of NADPH production has been shown to play a key role in this process. NADPH is recycled through reduction of NADP+ by several enzymatic systems in cells. However, de novo NADP+ is synthesized only through one known enzymatic reaction, catalyzed by NAD+ kinase (NADK). In this study, we show that oncogenic KRAS promotes protein kinase C (PKC)-mediated NADK phosphorylation, leading to its hyperactivation, thus sustaining both NADP+ and NADPH levels in PDAC cells. Together, our data show that increased NADK activity is an important adaptation driven by oncogenic signaling. Our findings indicate that NADK could serve as a much-needed therapeutic target for PDAC.

Keywords:  KRAS; NADK; NADP+; NADPH; PDAC; PKC

DOI:  https://doi.org/10.1016/j.celrep.2021.109238
Mol Biol Rep. 2021 Jun 16.

mTOR-Rictor-EGFR axis in oncogenesis and diagnosis of glioblastoma multiforme.

M Janaki Ramaiah, K Rohil Kumar.

  Glioblastoma multiforme (GBM) is one of the aggressive brain cancers with patients having less survival period upto 12-15 months. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase, belongs to the phosphatidylinositol 3-kinases (PI3K) pathway and is involved in various cellular processes of cancer cells. Cancer metabolism is regulated by mTOR and its components. mTOR forms two complexes as mTORC1 and mTORC2. Studies have identified the key component of the mTORC2 complex, Rapamycin-insensitive companion of mammalian target of rapamycin (Rictor) plays a prominent role in the regulation of cancer cell proliferation and metabolism. Apart, growth factor receptor signaling such as epidermal growth factor signaling mediated by epidermal growth factor receptor (EGFR) regulates cancer-related processes. In EGFR signaling various other signaling cascades such as phosphatidyl-inositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR pathway) and Ras/Raf/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) -dependent signaling cross-talk each other. From various studies about GBM, it is very well established that Rictor and EGFR mediated signaling pathways majorly playing a pivotal role in chemoresistance and tumor aggressiveness. Recent studies have shown that non-coding RNAs such as microRNAs (miRs) and long non-coding RNAs (lncRNAs) regulate the EGFR and Rictor and sensitize the cells towards chemotherapeutic agents. Thus, understanding of microRNA mediated regulation of EGFR and Rictor will help in cancer prevention and management as well as a future therapy.

Keywords:  EGFR; Glioblastoma multiforme (GBM); HDAC; Rictor; Temozolomide (TMZ); mTOR

DOI:  https://doi.org/10.1007/s11033-021-06462-2
Cold Spring Harb Perspect Med. 2021 Jun 14. pii: a037838. [Epub ahead of print]

Metabolic Phenotypes, Dependencies, and Adaptation in Lung Cancer.

Gina M DeNicola, David B Shackelford.

Lung cancer is a heterogeneous disease that is subdivided into histopathological subtypes with distinct behaviors. Each subtype is characterized by distinct features and molecular alterations that influence tumor metabolism. Alterations in tumor metabolism can be exploited by imaging modalities that use metabolite tracers for the detection and characterization of tumors. Microenvironmental factors, including nutrient and oxygen availability and the presence of stromal cells, are a critical influence on tumor metabolism. Recent technological advances facilitate the direct evaluation of metabolic alterations in patient tumors in this complex microenvironment. In addition, molecular alterations directly influence tumor cell metabolism and metabolic dependencies that influence response to therapy. Current therapeutic approaches to target tumor metabolism are currently being developed and translated into the clinic for patient therapy.

DOI: https://doi.org/10.1101/cshperspect.a037838
Chem Sci. 2020 Jul 29. 11(32): 8495-8501

A ratiometric fluorescent probe for real-time monitoring of intracellular glutathione fluctuations in response to cisplatin.

Hanzhuang Liu, Wenting Song, Shuren Zhang, Kin Shing Chan, Zijian Guo, Zhen Shen.

Real-time imaging of fluctuations in intracellular glutathione (GSH) concentrations is critical to understanding the mechanism of GSH-related cisplatin-resistance. Here, we describe a ratiometric fluorescence probe based on a reversible Michael addition reaction of GSH with the vinyl-functionalized boron-dipyrromethene (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene or BODIPY) 1. The probe was applied for real-time monitoring of the fluctuations in GSH levels in cells under cisplatin treatment. Notably, in cellular cisplatin-sensitive A549 cells, GSH concentrations rose until cell death, while in cisplatin-resistant cell lines, GSH levels first rose to the maximum then fell back to the initial concentration without significant apoptosis. These results indicate that different trends in GSH fluctuation can help distinguish cisplatin-resistant from cisplatin-sensitive cells. As such, this study has shown that probe 1 may potentially be used for real-time monitoring of intracellular GSH levels in response to therapeutics.

DOI: https://doi.org/10.1039/d0sc02889d
Biosci Rep. 2021 Jun 17. pii: BSR20211066. [Epub ahead of print]

Glucose regulates expression of pro-inflammatory genes IL-1β and IL-12 through a mechanism involving hexosamine biosynthesis pathway dependent regulation of αEcatenin.

Waruni C Dissanayake, Jin Kyo Oh, Brie Sorrenson, Peter R Shepherd.

  High glucose levels are associated with changes in macrophage polarization and evidence indicates that the sustained or even short-term high glucose levels modulate inflammatory responses in macrophages. However, the mechanism by which macrophages can sense the changes in glucose levels are not clearly understood. We find that high glucose levels rapidly increase the α-E catenin protein level in RAW264.7 macrophages. We also find an attenuation of glucose induced increase of α-E catenin when hexosamine biosynthesis pathway is inhibited either with glutamine depletion or with the drugs azaserine and tunicamycin. This indicates the involvement of hexosamine biosynthesis pathway in this process. Then, we investigated the potential role of α-E catenin in glucose induced macrophage polarization. We find that the reduction of α-E catenin level using siRNA attenuates the glucose induced changes of both IL-1β and IL-12 mRNA levels under LPS stimulated condition but does not affect TNF-α expression. Together this indicates that α-E catenin can sense the changes in glucose levels in macrophages via hexosamine biosynthesis pathway and also can modulate the glucose induced gene expression of inflammatory markers such as IL-1β and IL-12. This identifies a new part of the mechanism by which macrophages are able to respond to changes in glucose levels.

Keywords:  alpha catenin; hexosamine biosynthesis pathway; inflammation; macrophages

DOI:  https://doi.org/10.1042/BSR20211066