bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2021–01–31
twenty papers selected by
Ralitsa Radostinova Madsen, University College London
  1. G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling.
  2. Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer.
  3. The level of oncogenic Ras determines the malignant transformation of Lkb1 mutant tissue in vivo.
  4. NODAL/TGFβ signalling mediates the self-sustained stemness induced by PIK3CA H1047R homozygosity in pluripotent stem cells.
  5. A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance.
  6. Causal integration of multi-omics data with prior knowledge to generate mechanistic hypotheses.
  7. Preclinical evaluation and Phase 1b study of prexasertib, a CHK1 inhibitor, and samotolisib (LY3023414), a dual PI3K/mTOR inhibitor.
  8. A-769662 inhibits adipocyte glucose uptake in an AMPK-independent manner.
  9. Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission.
  10. Proliferative polyploid cells give rise to tumors via ploidy reduction.
  11. CBL mutations drive PI3K/AKT signaling via increased interaction with LYN and PIK3R1.
  12. Time-restricted feeding normalizes hyperinsulinemia to inhibit breast cancer in obese postmenopausal mouse models.
  13. New Insights into Oncogenic Transformation: Elevating Antioxidant and Nucleotide Levels Does the Trick.
  14. Proteotoxic stress is a driver of the loser status and cell competition.
  15. Ribosomopathy-associated mutations cause proteotoxic stress that is alleviated by TOR inhibition.
  16. Targeting BET proteins BRD2 and BRD3 in combination with PI3K-AKT inhibition as a therapeutic strategy for ovarian clear cell carcinoma.
  17. Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling.
  18. Cancer research needs a better map.
  19. A guide to understanding endoplasmic reticulum stress in metabolic disorders.
  20. Technical bias and the reproducibility crisis: The problem of systemic errors resulting from artefacts of equipment, methods or dataset has been underappreciated.
  1. Cell. 2021 Jan 18. pii: S0092-8674(20)31694-9. [Epub ahead of print]
    G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling.
    Genomics England Research Consortium
      Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling.
    Keywords:  G3BP1; G3BP2; TSC complex; cancer; lysosome; mTORC1; metabolism; neuronal function; stress granule
    DOI:  https://doi.org/10.1016/j.cell.2020.12.024
  2. Cancers (Basel). 2021 Jan 20. pii: E369. [Epub ahead of print]13(3):
    Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer.
    Aditi S Khatpe, Adedeji K Adebayo, Christopher A Herodotou, Brijesh Kumar, Harikrishna Nakshatri.
      Signaling from estrogen receptor alpha (ERα) and its ligand estradiol (E2) is critical for growth of ≈70% of breast cancers. Therefore, several drugs that inhibit ERα functions have been in clinical use for decades and new classes of anti-estrogens are continuously being developed. Although a significant number of ERα+ breast cancers respond to anti-estrogen therapy, ≈30% of these breast cancers recur, sometimes even after 20 years of initial diagnosis. Mechanism of resistance to anti-estrogens is one of the intensely studied disciplines in breast cancer. Several mechanisms have been proposed including mutations in ESR1, crosstalk between growth factor and ERα signaling, and interplay between cell cycle machinery and ERα signaling. ESR1 mutations as well as crosstalk with other signaling networks lead to ligand independent activation of ERα thus rendering anti-estrogens ineffective, particularly when treatment involved anti-estrogens that do not degrade ERα. As a result of these studies, several therapies that combine anti-estrogens that degrade ERα with PI3K/AKT/mTOR inhibitors targeting growth factor signaling or CDK4/6 inhibitors targeting cell cycle machinery are used clinically to treat recurrent ERα+ breast cancers. In this review, we discuss the nexus between ERα-PI3K/AKT/mTOR pathways and how understanding of this nexus has helped to develop combination therapies.
    Keywords:  PI3K-AKT-mTOR; anti-estrogen resistance; breast cancer; estrogen receptor
    DOI:  https://doi.org/10.3390/cancers13030369
  3. Commun Biol. 2021 Jan 29. 4(1): 142
    The level of oncogenic Ras determines the malignant transformation of Lkb1 mutant tissue in vivo.
    Briana Rackley, Chang-Soo Seong, Evan Kiely, Rebecca E Parker, Manali Rupji, Bhakti Dwivedi, John M Heddleston, William Giang, Neil Anthony, Teng-Leong Chew, Melissa Gilbert-Ross.
      The genetic and metabolic heterogeneity of RAS-driven cancers has confounded therapeutic strategies in the clinic. To address this, rapid and genetically tractable animal models are needed that recapitulate the heterogeneity of RAS-driven cancers in vivo. Here, we generate a Drosophila melanogaster model of Ras/Lkb1 mutant carcinoma. We show that low-level expression of oncogenic Ras (RasLow) promotes the survival of Lkb1 mutant tissue, but results in autonomous cell cycle arrest and non-autonomous overgrowth of wild-type tissue. In contrast, high-level expression of oncogenic Ras (RasHigh) transforms Lkb1 mutant tissue resulting in lethal malignant tumors. Using simultaneous multiview light-sheet microcopy, we have characterized invasion phenotypes of Ras/Lkb1 tumors in living larvae. Our molecular analysis reveals sustained activation of the AMPK pathway in malignant Ras/Lkb1 tumors, and demonstrate the genetic and pharmacologic dependence of these tumors on CaMK-activated Ampk. We further show that LKB1 mutant human lung adenocarcinoma patients with high levels of oncogenic KRAS exhibit worse overall survival and increased AMPK activation. Our results suggest that high levels of oncogenic KRAS is a driving event in the malignant transformation of LKB1 mutant tissue, and uncovers a vulnerability that may be used to target this aggressive genetic subset of RAS-driven tumors.
    DOI:  https://doi.org/10.1038/s42003-021-01663-8
  4. Dis Model Mech. 2021 Jan 28. pii: dmm.048298. [Epub ahead of print]
    NODAL/TGFβ signalling mediates the self-sustained stemness induced by PIK3CA H1047R homozygosity in pluripotent stem cells.
    Ralitsa R Madsen, James Longden, Rachel G Knox, Xavier Robin, Franziska Völlmy, Kenneth G Macleod, Larissa S Moniz, Neil O Carragher, Rune Linding, Bart Vanhaesebroeck, Robert K Semple.
      Activating PIK3CA mutations are known "drivers" of human cancer and developmental overgrowth syndromes. We recently demonstrated that the "hotspot" PIK3CA H1047R variant exerts unexpected allele dose-dependent effects on stemness in human pluripotent stem cells (hPSCs). In the present study, we combine high-depth transcriptomics, total proteomics and reverse-phase protein arrays to reveal potentially disease-related alterations in heterozygous cells, and to assess the contribution of activated TGFβ signalling to the stemness phenotype of homozygous PIK3CA H1047R cells. We demonstrate signalling rewiring as a function of oncogenic PI3K signalling strength, and provide experimental evidence that self-sustained stemness is causally related to enhanced autocrine NODAL/TGFβ signalling. A significant transcriptomic signature of TGFβ pathway activation in heterozygous PIK3CA H1047R was observed but was modest and was not associated with the stemness phenotype seen in homozygous mutants. Notably, the stemness gene expression in homozygous PIK3CA H1047R iPSCs was reversed by pharmacological inhibition of NODAL/TGFβ signalling, but not by pharmacological PI3Kα pathway inhibition. Altogether, this provides the first in-depth analysis of PI3K signalling in human pluripotent stem cells and directly links strong PI3K activation to developmental NODAL/TGFβ signalling. This work illustrates the importance of allele dosage and expression when artificial systems are used to model human genetic disease caused by activating PIK3CA mutations.
    Keywords:  PI3K; PIK3CA; Pluripotent stem cells; Stemness
    DOI:  https://doi.org/10.1242/dmm.048298
  5. Nat Chem Biol. 2021 Jan 25.
    A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance.
    Yuan Liu, Michael J Jurczak, Travis B Lear, Bo Lin, Mads B Larsen, Jason R Kennerdell, Yanwen Chen, Brydie R Huckestein, Matthew K Nguyen, Ferhan Tuncer, Yu Jiang, Satdarshan P Monga, Christopher P O'Donnell, Toren Finkel, Bill B Chen, Rama K Mallampalli.
      The adenosine monophosphate (AMP)-activated protein kinase (Ampk) is a central regulator of metabolic pathways, and increasing Ampk activity has been considered to be an attractive therapeutic target. Here, we have identified an orphan ubiquitin E3 ligase subunit protein, Fbxo48, that targets the active, phosphorylated Ampkα (pAmpkα) for polyubiquitylation and proteasomal degradation. We have generated a novel Fbxo48 inhibitory compound, BC1618, whose potency in stimulating Ampk-dependent signaling greatly exceeds 5-aminoimidazole-4-carboxamide-1-β-ribofuranoside (AICAR) or metformin. This compound increases the biological activity of Ampk not by stimulating the activation of Ampk, but rather by preventing activated pAmpkα from Fbxo48-mediated degradation. We demonstrate that, consistent with augmenting Ampk activity, BC1618 promotes mitochondrial fission, facilitates autophagy and improves hepatic insulin sensitivity in high-fat-diet-induced obese mice. Hence, we provide a unique bioactive compound that inhibits pAmpkα disposal. Together, these results define a new pathway regulating Ampk biological activity and demonstrate the potential utility of modulating this pathway for therapeutic benefit.
    DOI:  https://doi.org/10.1038/s41589-020-00723-0
  6. Mol Syst Biol. 2021 Jan;17(1): e9730
    Causal integration of multi-omics data with prior knowledge to generate mechanistic hypotheses.
    Aurelien Dugourd, Christoph Kuppe, Marco Sciacovelli, Enio Gjerga, Attila Gabor, Kristina B Emdal, Vitor Vieira, Dorte B Bekker-Jensen, Jennifer Kranz, Eric M J Bindels, Ana S H Costa, Abel Sousa, Pedro Beltrao, Miguel Rocha, Jesper V Olsen, Christian Frezza, Rafael Kramann, Julio Saez-Rodriguez.
      Multi-omics datasets can provide molecular insights beyond the sum of individual omics. Various tools have been recently developed to integrate such datasets, but there are limited strategies to systematically extract mechanistic hypotheses from them. Here, we present COSMOS (Causal Oriented Search of Multi-Omics Space), a method that integrates phosphoproteomics, transcriptomics, and metabolomics datasets. COSMOS combines extensive prior knowledge of signaling, metabolic, and gene regulatory networks with computational methods to estimate activities of transcription factors and kinases as well as network-level causal reasoning. COSMOS provides mechanistic hypotheses for experimental observations across multi-omics datasets. We applied COSMOS to a dataset comprising transcriptomics, phosphoproteomics, and metabolomics data from healthy and cancerous tissue from eleven clear cell renal cell carcinoma (ccRCC) patients. COSMOS was able to capture relevant crosstalks within and between multiple omics layers, such as known ccRCC drug targets. We expect that our freely available method will be broadly useful to extract mechanistic insights from multi-omics studies.
    Keywords:  causal reasoning; kidney cancer; metabolism; multi-omics; signaling
    DOI:  https://doi.org/10.15252/msb.20209730
  7. Clin Cancer Res. 2021 Jan 25. pii: clincanres.3242.2020. [Epub ahead of print]
    Preclinical evaluation and Phase 1b study of prexasertib, a CHK1 inhibitor, and samotolisib (LY3023414), a dual PI3K/mTOR inhibitor.
    David S Hong, Kathleen N Moore, Johanna C Bendell, Daniel Karp, Judy S Wang, Susanna V Ulahannan, Suzanne Jones, Wenjuan Wu, Gregory P Donoho, Yan Ding, Andrew Capen, Xuejing Aimee Wang, Aimee Bence Lin, Manish R Patel.
       PURPOSE: Prexasertib, a checkpoint kinase-I inhibitor (CHK1), exhibited modest monotherapy antitumor activity in previous studies. Preclinical data were generated to support the clinical combination of prexasertib+samotolisib, a phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor.
    EXPERIMENTAL DESIGN: Prexasertib+samotolisib was first evaluated in triple-negative breast cancer (TNBC) cells, MDA-MB-231 orthotopic xenograft tumors, and TNBC patient-derived-xenograft (PDX) mouse models. In the Phase 1b trial, following dose-escalation, the initial expansion arm (E1-solid tumors) explored prexasertib 105-mg/m2 intravenously every 14 days +samotolisib 200-mg orally twice-daily (BID). Subsequent expansion arms evaluated samotolisib 150-mg-BID in patients carrying PIK3CA mutations (E2-solid tumors) or with TNBC (E3). Safety and antitumor activity were assessed.
    RESULTS: Prexasertib+samotolisib inhibited proliferation in TNBC lines and primary tumor growth in the MDA-MB-231 model. Prexasertib+samotolisib exhibited synergistic or additive effects in 30/38 PDX single-mouse ("n=1") models, providing rationale for clinical evaluation. In the Phase 1b study, fifty-three patients were enrolled (Escalation:n=13; E1:n=9; E2:n=15; E3:n=16). No dose-limiting toxicities (DLTs) were observed during escalation; however, DLT-equivalent toxicities were observed in E1 leading to samotolisib dose reduction (150-mg-BID) in E2/E3. Common treatment-related adverse events were leukopenia/neutropenia (94.3%), thrombocytopenia (62.3%), and nausea (52.8%). During escalation, 2 patients achieved partial response for an overall response rate (ORR) of 15.4%, and ORRs were 13.3% for E2 (PIK3CA) and 25.0% for E3 (TNBC).
    CONCLUSIONS: Prexasertib+samotolisib showed antitumor activity in preclinical models and preliminary efficacy in heavily-pretreated patients. The clinical combination was associated with toxicity, suggesting supportive measures may be required. However, these data may inform future trials using other CHK1 and PI3K pathway inhibitors.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-3242
  8. Biochem J. 2021 Jan 25. pii: BCJ20200659. [Epub ahead of print]
    A-769662 inhibits adipocyte glucose uptake in an AMPK-independent manner.
    Franziska Kopietz, Yazeed Alshuweish, Silvia Bijland, Fatmah Alghamdi, Eva Degerman, Kei Sakamoto, Ian P Salt, Olga Göransson.
      Activation of AMP-activated protein kinase (AMPK) is considered a valid strategy for the treatment of type 2 diabetes. However, despite the importance of adipose tissue for whole-body energy homeostasis, the effect of AMPK activation in adipocytes has only been studied to a limited extent and mainly with the AMP-mimetic 5-aminoimidazole-4-carboxamide-1-b-d-ribofuranoside (AICAR), which has limited specificity. The aim of this study was to evaluate the effect of the allosteric AMPK activators A‑769662 and 991 on glucose uptake in adipocytes. For this purpose, primary rat or human adipocytes, and cultured 3T3-L1 adipocytes, were treated with either of the allosteric activators, or AICAR, and basal and insulin-stimulated glucose uptake was assessed. Additionally, the effect of AMPK activators on insulin-stimulated phosphorylation of Akt and Akt substrate of 160 kDa was assessed. Furthermore, primary adipocytes from ADaM site binding drug-resistant AMPKb1 S108A knock-in mice were employed to investigate specificity of the drugs for the observed effects. Our results show that insulin-stimulated adipocyte glucose uptake was significantly reduced by A‑769662 but not 991, yet neither activator had any clear effects on basal or insulin-stimulated Akt/AS160 signaling. The use of AMPKb1 S108A mutant-expressing adipocytes revealed that the observed inhibition of glucose uptake by A‑769662 is most likely AMPK-independent, a finding which is supported by the rapid inhibitory effect A-769662 exerts on glucose uptake in 3T3-L1 adipocytes. These data suggest that AMPK activation per se does not inhibit glucose uptake in adipocytes and that the effects of AICAR and A-769662 are AMPK-independent.
    Keywords:  A-769662; AMPK; AMPKbeta1 S108A; adipocytes; glucose uptake; insulin
    DOI:  https://doi.org/10.1042/BCJ20200659
  9. Proc Natl Acad Sci U S A. 2021 Feb 02. pii: e2020705118. [Epub ahead of print]118(5):
    Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission.
    Danilo De Gregorio, Jelena Popic, Justine P Enns, Antonio Inserra, Agnieszka Skalecka, Athanasios Markopoulos, Luca Posa, Martha Lopez-Canul, He Qianzi, Christopher K Lafferty, Jonathan P Britt, Stefano Comai, Argel Aguilar-Valles, Nahum Sonenberg, Gabriella Gobbi.
      Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT2A, but not N-methyl-D-aspartate (NMDA) and 5-HT1A, synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons (Raptor f/f :Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT2A/AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC (Raptor f/f :Gad2-Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.
    Keywords:  5-HT2A; AMPA; LSD; mTOR; social behavior
    DOI:  https://doi.org/10.1073/pnas.2020705118
  10. Nat Commun. 2021 01 28. 12(1): 646
    Proliferative polyploid cells give rise to tumors via ploidy reduction.
    Tomonori Matsumoto, Leslie Wakefield, Alexander Peters, Myron Peto, Paul Spellman, Markus Grompe.
      Polyploidy is a hallmark of cancer, and closely related to chromosomal instability involved in cancer progression. Importantly, polyploid cells also exist in some normal tissues. Polyploid hepatocytes proliferate and dynamically reduce their ploidy during liver regeneration. This raises the question whether proliferating polyploids are prone to cancer via chromosome missegregation during mitosis and/or ploidy reduction. Conversely polyploids could be resistant to tumor development due to their redundant genomes. Therefore, the tumor-initiation risk of physiologic polyploidy and ploidy reduction is still unclear. Using in vivo lineage tracing we here show that polyploid hepatocytes readily form liver tumors via frequent ploidy reduction. Polyploid hepatocytes give rise to regenerative nodules with chromosome aberrations, which are enhanced by ploidy reduction. Although polyploidy should theoretically prevent tumor suppressor loss, the high frequency of ploidy reduction negates this protection. Importantly, polyploid hepatocytes that undergo multiple rounds of cell division become predominantly mononucleated and are resistant to ploidy reduction. Our results suggest that ploidy reduction is an early step in the initiation of carcinogenesis from polyploid hepatocytes.
    DOI:  https://doi.org/10.1038/s41467-021-20916-y
  11. Blood. 2021 Jan 07. pii: blood.2020006528. [Epub ahead of print]
    CBL mutations drive PI3K/AKT signaling via increased interaction with LYN and PIK3R1.
    Roger Belizaire, Sebastian Hassan John Koochaki, Namrata D Udeshi, Alexis Vedder, Lei Sun, Tanya Svinkina, Christina Hartigan, Marie E McConkey, Veronica Kovalcik, Amanuel Bizuayehu, Caroline Stanclift, Monica Schenone, Steven A Carr, Eric Padron, Benjamin L Ebert.
      CBL encodes an E3 ubiquitin ligase and signaling adaptor that regulates receptor and non-receptor tyrosine kinases. Recurrent CBL mutations occur in myeloid neoplasms, including 10-20% of chronic myelomonocytic leukemia (CMML) cases, and selectively disrupt the protein's E3 ubiquitin ligase activity. CBL mutations have been associated with poor prognosis, but the oncogenic mechanisms and therapeutic implications of CBL mutations remain incompletely understood. We combined functional assays and global mass spectrometry to define the phosphoproteome, CBL interactome, and mechanism of signaling activation in a panel of cell lines expressing an allelic series of CBL mutations. Our analyses revealed that increased LYN activation and interaction with mutant CBL are key drivers of enhanced CBL phosphorylation, PIK3R1 recruitment, and downstream PI3K/AKT signaling in CBL-mutant cells. Signaling adaptor domains of CBL, including the tyrosine-kinase binding domain, proline-rich region, and C-terminal phosphotyrosine sites, were all required for the oncogenic function of CBL mutants. Genetic ablation or dasatinib-mediated inhibition of LYN reduced CBL phosphorylation, CBL-PIK3R1 interaction, and PI3K/AKT signaling. Furthermore, we demonstrated in vitro and in vivo antiproliferative efficacy of dasatinib in CBL-mutant cell lines and primary CMML. Overall, these mechanistic insights into the molecular function of CBL mutations provide rationale to explore the therapeutic potential of LYN inhibition in CBL-mutant myeloid malignancies.
    DOI:  https://doi.org/10.1182/blood.2020006528
  12. Nat Commun. 2021 01 25. 12(1): 565
    Time-restricted feeding normalizes hyperinsulinemia to inhibit breast cancer in obese postmenopausal mouse models.
    Manasi Das, Lesley G Ellies, Deepak Kumar, Consuelo Sauceda, Alexis Oberg, Emilie Gross, Tyler Mandt, Isabel G Newton, Mehak Kaur, Dorothy D Sears, Nicholas J G Webster.
      Accumulating evidence indicates that obesity with its associated metabolic dysregulation, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers including postmenopausal breast cancer. Caloric restriction can ameliorate the harmful metabolic effects of obesity and inhibit cancer progression but is difficult to implement and maintain outside of the clinic. In this study, we aim to test a time-restricted feeding (TRF) approach on mouse models of obesity-driven postmenopausal breast cancer. We show that TRF abrogates the obesity-enhanced mammary tumor growth in two orthotopic models in the absence of calorie restriction or weight loss. TRF also reduces breast cancer metastasis to the lung. Furthermore, TRF delays tumor initiation in a transgenic model of mammary tumorigenesis prior to the onset of obesity. Notably, TRF increases whole-body insulin sensitivity, reduces hyperinsulinemia, restores diurnal gene expression rhythms in the tumor, and attenuates tumor growth and insulin signaling. Importantly, inhibition of insulin secretion with diazoxide mimics TRF whereas artificial elevation of insulin through insulin pumps implantation reverses the effect of TRF, suggesting that TRF acts through modulating hyperinsulinemia. Our data suggest that TRF is likely to be effective in breast cancer prevention and therapy.
    DOI:  https://doi.org/10.1038/s41467-020-20743-7
  13. Trends Cancer. 2021 Jan 23. pii: S2405-8033(21)00016-9. [Epub ahead of print]
    New Insights into Oncogenic Transformation: Elevating Antioxidant and Nucleotide Levels Does the Trick.
    Rushendhiran Kesavan, Halie Rion, Gerta Hoxhaj.
      The molecular elements that govern cellular transformation and tumorigenic competence remain poorly understood. Metabolic reprogramming has emerged as a hallmark of malignant transformation. Recently in Cell Metabolism, Zhang et al. showed that an increase of cellular antioxidant capacity and nucleotide availability is sufficient to induce oncogenic transformation and tumorigenesis.
    DOI:  https://doi.org/10.1016/j.trecan.2021.01.003
  14. Nat Cell Biol. 2021 Jan 25.
    Proteotoxic stress is a driver of the loser status and cell competition.
    Michael E Baumgartner, Michael P Dinan, Paul F Langton, Iwo Kucinski, Eugenia Piddini.
      Cell competition allows winner cells to eliminate less fit loser cells in tissues. In Minute cell competition, cells with a heterozygous mutation in ribosome genes, such as RpS3+/- cells, are eliminated by wild-type cells. How cells are primed as losers is partially understood and it has been proposed that reduced translation underpins the loser status of ribosome mutant, or Minute, cells. Here, using Drosophila, we show that reduced translation does not cause cell competition. Instead, we identify proteotoxic stress as the underlying cause of the loser status for Minute competition and competition induced by mahjong, an unrelated loser gene. RpS3+/- cells exhibit reduced autophagic and proteasomal flux, accumulate protein aggregates and can be rescued from competition by improving their proteostasis. Conversely, inducing proteotoxic stress is sufficient to turn otherwise wild-type cells into losers. Thus, we propose that tissues may preserve their health through a proteostasis-based mechanism of cell competition and cell selection.
    DOI:  https://doi.org/10.1038/s41556-020-00627-0
  15. Nat Cell Biol. 2021 Jan 25.
    Ribosomopathy-associated mutations cause proteotoxic stress that is alleviated by TOR inhibition.
    Carles Recasens-Alvarez, Cyrille Alexandre, Joanna Kirkpatrick, Hisashi Nojima, David J Huels, Ambrosius P Snijders, Jean-Paul Vincent.
      Ribosomes are multicomponent molecular machines that synthesize all of the proteins of living cells. Most of the genes that encode the protein components of ribosomes are therefore essential. A reduction in gene dosage is often viable albeit deleterious and is associated with human syndromes, which are collectively known as ribosomopathies1-3. The cell biological basis of these pathologies has remained unclear. Here, we model human ribosomopathies in Drosophila and find widespread apoptosis and cellular stress in the resulting animals. This is not caused by insufficient protein synthesis, as reasonably expected. Instead, ribosomal protein deficiency elicits proteotoxic stress, which we suggest is caused by the accumulation of misfolded proteins that overwhelm the protein degradation machinery. We find that dampening the integrated stress response4 or autophagy increases the harm inflicted by ribosomal protein deficiency, suggesting that these activities could be cytoprotective. Inhibition of TOR activity-which decreases ribosomal protein production, slows down protein synthesis and stimulates autophagy5-reduces proteotoxic stress in our ribosomopathy model. Interventions that stimulate autophagy, combined with means of boosting protein quality control, could form the basis of a therapeutic strategy for this class of diseases.
    DOI:  https://doi.org/10.1038/s41556-020-00626-1
  16. Mol Cancer Ther. 2021 Jan 28. pii: molcanther.0809.2020. [Epub ahead of print]
    Targeting BET proteins BRD2 and BRD3 in combination with PI3K-AKT inhibition as a therapeutic strategy for ovarian clear cell carcinoma.
    Shogo Shigeta, Goldie Y L Lui, Reid Shaw, Russell Moser, Kay E Gurley, Grace Durenberger, Rachele Rosati, Robert L Diaz, Tan A Ince, Elizabeth M Swisher, Carla Grandori, Christopher J Kemp.
      Ovarian clear cell carcinoma (OCCC) is a rare, chemo-resistant subtype of ovarian cancer. To identify novel therapeutic targets and combination therapies for OCCC, we subjected a set of patient-derived ovarian cancer cell lines to arrayed high throughput siRNA and drug screening. The results indicated OCCC cells are vulnerable to knockdown of epigenetic gene targets such as bromodomain and extra-terminal domain (BET) proteins BRD2 and BRD3. Subsequent RNA interference assays, as well as BET inhibitor treatments validated these BET proteins as potential therapeutic targets. Because development of resistance to single targeted agents is common, we next performed sensitizer drug screens to identify potential combination therapies with the BET inhibitor CPI0610. Several PI3K or AKT inhibitors were among the top drug combinations identified and subsequent work showed CPI0610 synergized with alpelisib or MK2206 by inducing p53-independent apoptosis. We further verified synergy between CPI0610 and PI3K-AKT pathway inhibitors alpelisib, MK2206, or ipatasertib in tumor organoids obtained directly from OCCC patients. These findings indicate further preclinical evaluation of BET inhibitors, alone or in combination with PI3K-AKT inhibitors for OCCC is warranted.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-20-0809
  17. Front Cell Dev Biol. 2020 ;8 608044
    Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling.
    Stefanie Chan, Emma Smith, Yuan Gao, Julian Kwan, Benjamin C Blum, Andrew M Tilston-Lunel, Isabella Turcinovic, Xaralabos Varelas, Maria Dafne Cardamone, Stefano Monti, Andrew Emili, Valentina Perissi.
      G Protein Suppressor 2 (GPS2) is a multifunctional protein that exerts important roles in inflammation and metabolism in adipose, liver, and immune cells. GPS2 has recently been identified as a significantly mutated gene in breast cancer and other malignancies and proposed to work as a putative tumor suppressor. However, molecular mechanisms by which GPS2 prevents cancer development and/or progression are largely unknown. Here, we have profiled the phenotypic changes induced by GPS2 depletion in MDA-MB-231 triple negative breast cancer cells and investigated the underlying molecular mechanisms. We found that GPS2-deleted MDA-MB-231 cells exhibited increased proliferative, migratory, and invasive properties in vitro, and conferred greater tumor burden in vivo in an orthotopic xenograft mouse model. Transcriptomic, proteomic and phospho-proteomic profiling of GPS2-deleted MBA-MB-231 revealed a network of altered signals that relate to cell growth and PI3K/AKT signaling. Overlay of GPS2-regulated gene expression with MDA-MB-231 cells modified to express constitutively active AKT showed significant overlap, suggesting that sustained AKT activation is associated with loss of GPS2. Accordingly, we demonstrate that the pro-oncogenic phenotypes associated with GPS2 deletion are rescued by pharmacological inhibition of AKT with MK2206. Collectively, these observations confirm a tumor suppressor role for GPS2 and reveal that loss of GPS2 promotes breast cancer cell proliferation and tumor growth through uncontrolled activation of AKT signaling. Moreover, our study points to GPS2 as a potential biomarker for a subclass of breast cancers that would be responsive to PI3K-class inhibitor drugs.
    Keywords:  Akt; GPS2; MK2206 (PubChem CID: 46930998); breast cancer; ubiquitin (Ub)
    DOI:  https://doi.org/10.3389/fcell.2020.608044
  18. Nature. 2021 Jan;589(7843): 514-516
    Cancer research needs a better map.
    Jesse S Boehm, Mathew J Garnett, David J Adams, Hayley E Francies, Todd R Golub, William C Hahn, Francesco Iorio, James M McFarland, Leopold Parts, Francisca Vazquez.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-021-00182-0
  19. Mol Metab. 2021 Jan 20. pii: S2212-8778(21)00009-0. [Epub ahead of print] 101169
    A guide to understanding endoplasmic reticulum stress in metabolic disorders.
    Imke L Lemmer, Nienke Willemsen, Nazia Hilal, Alexander Bartelt.
       BACKGROUND: The global rise of metabolic disorders, such as obesity, diabetes type 2 and cardiovascular disease, demands a thorough molecular understanding of the cellular mechanisms that govern health or disease. The endoplasmic reticulum (ER) is a key organelle for cellular function and metabolic adaptation and, therefore, disturbed ER function, "ER stress", is a key feature of metabolic disorders.
    SCOPE OF REVIEW: As ER stress remains an ill-defined phenomenon, this review provides a general guide to understanding the nature, aetiology and consequences of ER stress in metabolic disorders. We define ER stress by its type of stressor, which is driven by proteotoxicity, lipotoxicity, and/or glucotoxicity. We discuss the implications of ER stress in metabolic disorders by reviewing evidence implicating ER phenotypes and organelle communication, protein quality control, calcium homeostasis, lipid and carbohydrate metabolism, and inflammation as key mechanisms in the development of ER stress and metabolic dysfunction.
    MAJOR CONCLUSIONS: In mammalian biology, ER is a phenotypically and functionally diverse platform for nutrient sensing, which is critical for cell-type specific metabolic control by e.g. hepatocytes, adipocytes, muscle cells, and neurons. In these cells, ER stress is a distinct, transient state of functional imbalance, which is usually resolved by the activation of adaptive programs such as the unfolded protein response (UPR), ER-associated protein degradation (ERAD), or autophagy. However, challenges to proteostasis also impact lipid and glucose metabolism and vice versa. In the ER, both sensing and adaptive measures are integrated and failure of the ER to adapt leads to aberrant metabolism, organelle dysfunction, insulin resistance, and inflammation. In conclusion, the ER is intricately linked to a wide spectrum of cellular functions and is a critical component in maintaining and restoring metabolic health.
    Keywords:  ERAD; NFE2L1; Obesity; UPR; UPS; autophagy; calcium homeostasis; diabetes; endoplasmic reticulum; glucotoxicity; inflammation; lipid metabolism; lipotoxicity; proteostasis; proteotoxicity
    DOI:  https://doi.org/10.1016/j.molmet.2021.101169
  20. EMBO Rep. 2021 Jan 25. e52327
    Technical bias and the reproducibility crisis: The problem of systemic errors resulting from artefacts of equipment, methods or dataset has been underappreciated.
    Philip Hunter.
      Technical bias can cause lack of reproducibility. While harder to identify than other bias, it can cause consistent systemic errors in experimental data and analysis.
    DOI:  https://doi.org/10.15252/embr.202052327
This page is being maintained by Thomas Krichel. It was last updated on 2024‒12‒15 at 1:54.