bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2022‒05‒08
eighteen papers selected by
Ralitsa Radostinova Madsen
University College London Cancer Institute
  1. Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs.
  2. Trans-omics analysis of insulin action reveals a cell growth subnetwork which co-regulates anabolic processes.
  3. PTEN differentially regulates endocytosis, migration, and proliferation in the enteric protozoan parasite Entamoeba histolytica.
  4. Structural insights into Ras regulation by SIN1.
  5. Coping with starvation: Cysteine keeps mTORC1 suppressed to ensure survival.
  6. Distinctive molecular features of regenerative stem cells in the damaged male germline.
  7. De Novo Labeling and Trafficking of Individual Lipid Species in Live Cells.
  8. PI3K Signaling in Dendritic Cells Aggravates DSS-Induced Colitis.
  9. A multicenter, dose-finding, phase 1b study of imatinib in combination with alpelisib as third-line treatment in patients with advanced gastrointestinal stromal tumor.
  10. Multi-omics single-cell data integration and regulatory inference with graph-linked embedding.
  11. Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
  12. The Mettl3 epitranscriptomic writer amplifies p53 stress responses.
  13. Lineage tracing reveals the phylodynamics, plasticity, and paths of tumor evolution.
  14. Protein degradation sets the fraction of active ribosomes at vanishing growth.
  15. Short term treatment with a cocktail of rapamycin, acarbose and phenylbutyrate delays aging phenotypes in mice.
  16. eEF2K activity determines synergy to co-treatment of cancer cells with PI3K and MEK inhibitors.
  17. Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice.
  18. Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism.
  1. Nature. 2022 May 04.
    Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs.
    Simon Eschweiler, Ciro Ramírez-Suástegui, Yingcong Li, Emma King, Lindsey Chudley, Jaya Thomas, Oliver Wood, Adrian von Witzleben, Danielle Jeffrey, Katy McCann, Hayley Simon, Monalisa Mondal, Alice Wang, Martina Dicker, Elena Lopez-Guadamillas, Ting-Fang Chou, Nicola A Dobbs, Louisa Essame, Gary Acton, Fiona Kelly, Gavin Halbert, Joseph J Sacco, Andrew Graeme Schache, Richard Shaw, James Anthony McCaul, Claire Paterson, Joseph H Davies, Peter A Brennan, Rabindra P Singh, Paul M Loadman, William Wilson, Allan Hackshaw, Gregory Seumois, Klaus Okkenhaug, Gareth J Thomas, Terry M Jones, Ferhat Ay, Greg Friberg, Mitchell Kronenberg, Bart Vanhaesebroeck, Pandurangan Vijayanand, Christian H Ottensmeier.
      Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1-3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.
    DOI:  https://doi.org/10.1038/s41586-022-04685-2
  2. iScience. 2022 May 20. 25(5): 104231
    Trans-omics analysis of insulin action reveals a cell growth subnetwork which co-regulates anabolic processes.
    Akira Terakawa, Yanhui Hu, Toshiya Kokaji, Katsuyuki Yugi, Keigo Morita, Satoshi Ohno, Yifei Pan, Yunfan Bai, Andrey A Parkhitko, Xiaochun Ni, John M Asara, Martha L Bulyk, Norbert Perrimon, Shinya Kuroda.
      Insulin signaling promotes anabolic metabolism to regulate cell growth through multi-omic interactions. To obtain a comprehensive view of the cellular responses to insulin, we constructed a trans-omic network of insulin action in Drosophila cells that involves the integration of multi-omic data sets. In this network, 14 transcription factors, including Myc, coordinately upregulate the gene expression of anabolic processes such as nucleotide synthesis, transcription, and translation, consistent with decreases in metabolites such as nucleotide triphosphates and proteinogenic amino acids required for transcription and translation. Next, as cell growth is required for cell proliferation and insulin can stimulate proliferation in a context-dependent manner, we integrated the trans-omic network with results from a CRISPR functional screen for cell proliferation. This analysis validates the role of a Myc-mediated subnetwork that coordinates the activation of genes involved in anabolic processes required for cell growth.
    Keywords:  In silico biology; Omics; Systems biology
    DOI:  https://doi.org/10.1016/j.isci.2022.104231
  3. PLoS Pathog. 2022 May 02. 18(5): e1010147
    PTEN differentially regulates endocytosis, migration, and proliferation in the enteric protozoan parasite Entamoeba histolytica.
    Samia Kadri, Kumiko Nakada-Tsukui, Natsuki Watanabe, Ghulam Jeelani, Tomoyoshi Nozaki.
      PTEN is a lipid phosphatase that is highly conserved and involved in a broad range of biological processes including cytoskeletal reorganization, endocytosis, signal transduction, and cell migration in all eukaryotes. Although regulation of phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] signaling via PTEN has been well established in model organisms and mammals, it remains elusive in the parasitic protist E. histolytica, which heavily relies on PtdIns phosphate(s)-dependent membrane traffic, migration, and phago- and trogocytosis for its pathogenesis. In this study, we characterized the major PTEN from E. histolytica, EhPTEN1, which shows the highest expression at the transcript level in the trophozoite stage among 6 possible PTENs, to understand the significance of PtdIns(3,4,5)P3 signaling in this parasite. Live imaging of GFP-EhPTEN1 expressing amebic trophozoites showed localization mainly in the cytosol with a higher concentration at pseudopods and the extending edge of the phago- and trogocytic cups. Furthermore, quantitative analysis of phago- and trogocytosis using a confocal image cytometer showed that overexpression of EhPTEN1 caused reduction in trogo- and phagocytosis while transcriptional gene silencing of EhPTEN1 gene caused opposite phenotypes. These data suggest that EhPTEN1 has an inhibitory role in these biological processes. Conversely, EhPTEN1 acts as a positive regulator for fluid-phase and receptor-mediated endocytosis in E. histolytica trophozoites. Moreover, we showed that EhPTEN1 was required for optimal growth and migration of this parasite. Finally, the phosphatase activity of EhPTEN1 towards PtdIns(3,4,5)P3 was demonstrated, suggesting that the biological roles of EhPTEN1 are likely linked to its catalytic function. Taken together, these results indicate that EhPTEN1 differentially regulates multiple cellular activities essential for proliferation and pathogenesis of the organism, via PtdIns(3,4,5)P3 signaling. Elucidation of biological roles of PTEN and PtdIns(3,4,5)P3 signaling at the molecular levels promotes our understanding of the pathogenesis of this parasite.
    DOI:  https://doi.org/10.1371/journal.ppat.1010147
  4. Proc Natl Acad Sci U S A. 2022 May 10. 119(19): e2119990119
    Structural insights into Ras regulation by SIN1.
    Yuyuan Zheng, Lei Ding, Xianhui Meng, Meg Potter, Alison L Kearney, Jie Zhang, Jie Sun, David E James, Guang Yang, Chun Zhou.
      SignificanceBoth the mTORC2 and Ras-ERK pathways respond to growth factor stimulation and play critical roles in cell growth and proliferation, disarray of these pathways leads to many diseases, especially cancer. These two signaling pathways crosstalk at many levels; recently it's become clear that the SIN1 component of mTORC2 could interact with Ras family small GTPases, but how these two proteins interact at the molecular level and the functional outcomes of this interaction remain to be addressed. In this work we determined the high-resolution structure of Ras-SIN1 complexes and revealed the detailed interaction mechanism. We also showed that Ras-SIN1 association inhibits insulin-induced ERK activation. Insights from this work could improve our understanding of the disease-causing mechanism of errant mTORC2 or Ras proteins.
    Keywords:  PI3K; Ras; SIN1; insulin; mTORC2
    DOI:  https://doi.org/10.1073/pnas.2119990119
  5. Mol Cell. 2022 May 05. pii: S1097-2765(22)00375-6. [Epub ahead of print]82(9): 1613-1615
    Coping with starvation: Cysteine keeps mTORC1 suppressed to ensure survival.
    Dohun Kim, Gerta Hoxhaj.
      Jouandin et al. (2022) show that lysosomal-derived cysteine serves as a signal to promote the tricarboxylic acid (TCA) cycle and suppress TORC1 signaling for Drosophila to endure starvation periods.
    DOI:  https://doi.org/10.1016/j.molcel.2022.04.018
  6. Nat Commun. 2022 May 06. 13(1): 2500
    Distinctive molecular features of regenerative stem cells in the damaged male germline.
    Hue M La, Jinyue Liao, Julien M D Legrand, Fernando J Rossello, Ai-Leen Chan, Vijesh Vaghjiani, Jason E Cain, Antonella Papa, Tin Lap Lee, Robin M Hobbs.
      Maintenance of male fertility requires spermatogonial stem cells (SSCs) that self-renew and generate differentiating germ cells for production of spermatozoa. Germline cells are sensitive to genotoxic drugs and patients receiving chemotherapy can become infertile. SSCs surviving treatment mediate germline recovery but pathways driving SSC regenerative responses remain poorly understood. Using models of chemotherapy-induced germline damage and recovery, here we identify unique molecular features of regenerative SSCs and characterise changes in composition of the undifferentiated spermatogonial pool during germline recovery by single-cell analysis. Increased mitotic activity of SSCs mediating regeneration is accompanied by alterations in growth factor signalling including PI3K/AKT and mTORC1 pathways. While sustained mTORC1 signalling is detrimental for SSC maintenance, transient mTORC1 activation is critical for the regenerative response. Concerted inhibition of growth factor signalling disrupts core features of the regenerative state and limits germline recovery. We also demonstrate that the FOXM1 transcription factor is a target of growth factor signalling in undifferentiated spermatogonia and provide evidence for a role in regeneration. Our data confirm dynamic changes in SSC functional properties following damage and support an essential role for microenvironmental growth factors in promoting a regenerative state.
    DOI:  https://doi.org/10.1038/s41467-022-30130-z
  7. Mol Metab. 2022 Apr 30. pii: S2212-8778(22)00080-1. [Epub ahead of print] 101511
    De Novo Labeling and Trafficking of Individual Lipid Species in Live Cells.
    Jun Zhang, Jia Nie, Haoran Sun, Jie Li, John-Paul Andersen, Yuguang Shi.
      Lipids exert dynamic biological functions which are determined both by their fatty acyl compositions and spatiotemporal distributions inside the cell. However, it remains a daunting task to investigate any of these features for each of the more than 1000 lipid species due to a lack of a universal labeling method for individual lipid moieties in live cells. Here we report a de novo lipid labeling method for individual lipid species with precise acyl compositions in live cells. The method is based on the principle of de novo lipid remodeling of exogenously added lysolipids with fluorescent acyl-CoA, leading to the re-synthesis of fluorescence-labeled lipids which can be imaged by confocal microscopy. In contrast to exogenously labeled lipids, the de novo labeled lipids retained full biological properties of their endogenous counterparts, including subcellular localization, trafficking, and recognition by lipid transporters. This method afforded us the opportunity to uncover some unexpected features of newly remodeled lipids and their transporters that were previously missed by conventional methods. Together, this method not only provides a powerful tool for functional analysis of individual lipid species and lipid transporters, but also calls for re-evaluation of previously published results using exogenously labeled lipids.
    Keywords:  Lipid remodeling; Lipid trafficking; NBD; Phospholipid Transporters
    DOI:  https://doi.org/10.1016/j.molmet.2022.101511
  8. Front Immunol. 2022 ;13 695576
    PI3K Signaling in Dendritic Cells Aggravates DSS-Induced Colitis.
    Mario Kuttke, Dominika Hromadová, Ceren Yildirim, Julia S Brunner, Andrea Vogel, Hannah Paar, Sophie Peters, Maria Weber, Melanie Hofmann, Martina Kerndl, Markus Kieler, Hannes Datler, Laszlo Musiejovsky, Manuel Salzmann, Michaela Lang, Klara Soukup, Angela Halfmann, Omar Sharif, Gernot Schabbauer.
      Aberrant innate immune responses to the gut microbiota are causally involved in the pathogenesis of inflammatory bowel diseases (IBD). The exact triggers and main signaling pathways activating innate immune cells and how they modulate adaptive immunity in IBD is still not completely understood. Here, we report that the PI3K/PTEN signaling pathway in dendritic cells enhances IL-6 production in a model of DSS-induced colitis. This results in exacerbated Th1 cell responses and increased mortality in DC-specific PTEN knockout (PTENΔDC) animals. Depletion of the gut microbiota using antibiotics as well as blocking IL-6R signaling rescued mortality in PTENΔDC mice, whereas adoptive transfer of Flt3L-derived PTEN-/- DCs into WT recipients exacerbated DSS-induced colitis and increased mortality. Taken together, we show that the PI3K signaling pathway in dendritic cells contributes to disease pathology by promoting IL-6 mediated Th1 responses.
    Keywords:  DSS-induced colitis; Interleukin-6; PI3K; PTEN; Th1-response; dendritic cells
    DOI:  https://doi.org/10.3389/fimmu.2022.695576
  9. BMC Cancer. 2022 May 06. 22(1): 511
    A multicenter, dose-finding, phase 1b study of imatinib in combination with alpelisib as third-line treatment in patients with advanced gastrointestinal stromal tumor.
    Maria A Pantaleo, Michael C Heinrich, Antoine Italiano, Claudia Valverde, Patrick Schöffski, Giovanni Grignani, Anna K L Reyners, Sebastian Bauer, Peter Reichardt, Daniel Stark, Ghimja Berhanu, Ulrike Brandt, Tommaso Stefanelli, Hans Gelderblom.
      BACKGROUND: Acquired resistance to approved tyrosine kinase inhibitors limits their clinical use in patients with gastrointestinal stromal tumor (GIST). This study investigated the safety, tolerability and efficacy of alpelisib, a phosphatidylinositol 3-kinase inhibitor, used in combination with imatinib in patients with advanced GIST who had failed prior therapy with both imatinib and sunitinib.METHODS: This phase 1b, multicenter, open-label study consisted of 2 phases: dose escalation and dose expansion. Dose escalation involved 200 mg once daily (QD) alpelisib, initially, followed by 250 and 350 mg. These were combined with 400 mg QD imatinib until maximum tolerated dose (MTD) and/or a recommended phase 2 dose (RP2D) of alpelisib in combination with imatinib was determined. This MTD/RP2D dose was tested to evaluate the clinical activity of this combination in dose expansion.
    RESULTS: Fifty-six patients were enrolled, 21 and 35 in the dose escalation and expansion phases, respectively. The MTD of alpelisib given with imatinib was determined as 350 mg QD. Combination treatment showed partial response in 1 (2.9%) and stable disease in 15 (42.9%) patients. Median progression-free survival was 2 months (95% CI 1.8-4.6). Overall, 92.9% patients had adverse events (AEs) while 46.4% had grade 3/4 AEs, hyperglycemia being the most common (23.2%).
    CONCLUSIONS: The MTD of alpelisib was estimated as 350 mg QD when used in combination with imatinib 400 mg QD after oral administration in patients with advanced GIST. The safety and tolerability profile of this combination was acceptable; however, the combination did not demonstrate sufficient clinical activity to justify additional clinical testing.
    TRIAL REGISTRATION: ClinicalTrials.gov NCT01735968 (date of initial registration 28/11/2012).
    Keywords:  Alpelisib; GIST; Gastrointestinal stromal tumor; Imatinib; Regorafenib; Sunitinib
    DOI:  https://doi.org/10.1186/s12885-022-09610-4
  10. Nat Biotechnol. 2022 May 02.
    Multi-omics single-cell data integration and regulatory inference with graph-linked embedding.
    Zhi-Jie Cao, Ge Gao.
      Despite the emergence of experimental methods for simultaneous measurement of multiple omics modalities in single cells, most single-cell datasets include only one modality. A major obstacle in integrating omics data from multiple modalities is that different omics layers typically have distinct feature spaces. Here, we propose a computational framework called GLUE (graph-linked unified embedding), which bridges the gap by modeling regulatory interactions across omics layers explicitly. Systematic benchmarking demonstrated that GLUE is more accurate, robust and scalable than state-of-the-art tools for heterogeneous single-cell multi-omics data. We applied GLUE to various challenging tasks, including triple-omics integration, integrative regulatory inference and multi-omics human cell atlas construction over millions of cells, where GLUE was able to correct previous annotations. GLUE features a modular design that can be flexibly extended and enhanced for new analysis tasks. The full package is available online at https://github.com/gao-lab/GLUE .
    DOI:  https://doi.org/10.1038/s41587-022-01284-4
  11. Cell. 2022 Apr 27. pii: S0092-8674(22)00461-5. [Epub ahead of print]
    Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
    Xiulei Mo, Qiankun Niu, Andrey A Ivanov, Yiu Huen Tsang, Cong Tang, Changfa Shu, Qianjin Li, Kun Qian, Alafate Wahafu, Sean P Doyle, Danielle Cicka, Xuan Yang, Dacheng Fan, Matthew A Reyna, Lee A D Cooper, Carlos S Moreno, Wei Zhou, Taofeek K Owonikoko, Sagar Lonial, Fadlo R Khuri, Yuhong Du, Suresh S Ramalingam, Gordon B Mills, Haian Fu.
      Comprehensive sequencing of patient tumors reveals genomic mutations across tumor types that enable tumorigenesis and progression. A subset of oncogenic driver mutations results in neomorphic activity where the mutant protein mediates functions not engaged by the parental molecule. Here, we identify prevalent variant-enabled neomorph-protein-protein interactions (neoPPI) with a quantitative high-throughput differential screening (qHT-dS) platform. The coupling of highly sensitive BRET biosensors with miniaturized coexpression in an ultra-HTS format allows large-scale monitoring of the interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells. The screening of 17,792 interactions with 2,172,864 data points revealed a landscape of gain of interactions encompassing both oncogenic and tumor suppressor mutations. For example, the recurrent BRAF V600E lesion mediates KEAP1 neoPPI, rewiring a BRAFV600E/KEAP1 signaling axis and creating collateral vulnerability to NQO1 substrates, offering a combination therapeutic strategy. Thus, cancer genomic alterations can create neo-interactions, informing variant-directed therapeutic approaches for precision medicine.
    Keywords:  BRET(n); cancer genomics; cancer target; driver mutations; interactome; neoPPI; oncogene; protein-protein interaction; systems biology; tumor suppressor
    DOI:  https://doi.org/10.1016/j.cell.2022.04.014
  12. Mol Cell. 2022 Apr 27. pii: S1097-2765(22)00321-5. [Epub ahead of print]
    The Mettl3 epitranscriptomic writer amplifies p53 stress responses.
    Nitin Raj, Mengxiong Wang, Jose A Seoane, Richard L Zhao, Alyssa M Kaiser, Nancie A Moonie, Janos Demeter, Anthony M Boutelle, Craig H Kerr, Abigail S Mulligan, Clare Moffatt, Shelya X Zeng, Hua Lu, Maria Barna, Christina Curtis, Howard Y Chang, Peter K Jackson, Laura D Attardi.
      The p53 transcription factor drives anti-proliferative gene expression programs in response to diverse stressors, including DNA damage and oncogenic signaling. Here, we seek to uncover new mechanisms through which p53 regulates gene expression using tandem affinity purification/mass spectrometry to identify p53-interacting proteins. This approach identified METTL3, an m6A RNA-methyltransferase complex (MTC) constituent, as a p53 interactor. We find that METTL3 promotes p53 protein stabilization and target gene expression in response to DNA damage and oncogenic signals, by both catalytic activity-dependent and independent mechanisms. METTL3 also enhances p53 tumor suppressor activity in in vivo mouse cancer models and human cancer cells. Notably, METTL3 only promotes tumor suppression in the context of intact p53. Analysis of human cancer genome data further supports the notion that the MTC reinforces p53 function in human cancer. Together, these studies reveal a fundamental role for METTL3 in amplifying p53 signaling in response to cellular stress.
    Keywords:  DNA damage; METTL14; METTL3; N(6)-methyladenosine (m6A) modification; epitranscriptomics; lung cancer; mass spectrometry; methyltransferase complex; p53; tumor suppressor
    DOI:  https://doi.org/10.1016/j.molcel.2022.04.010
  13. Cell. 2022 Apr 28. pii: S0092-8674(22)00462-7. [Epub ahead of print]
    Lineage tracing reveals the phylodynamics, plasticity, and paths of tumor evolution.
    Dian Yang, Matthew G Jones, Santiago Naranjo, William M Rideout, Kyung Hoi Joseph Min, Raymond Ho, Wei Wu, Joseph M Replogle, Jennifer L Page, Jeffrey J Quinn, Felix Horns, Xiaojie Qiu, Michael Z Chen, William A Freed-Pastor, Christopher S McGinnis, David M Patterson, Zev J Gartner, Eric D Chow, Trever G Bivona, Michelle M Chan, Nir Yosef, Tyler Jacks, Jonathan S Weissman.
      Tumor evolution is driven by the progressive acquisition of genetic and epigenetic alterations that enable uncontrolled growth and expansion to neighboring and distal tissues. The study of phylogenetic relationships between cancer cells provides key insights into these processes. Here, we introduced an evolving lineage-tracing system with a single-cell RNA-seq readout into a mouse model of Kras;Trp53(KP)-driven lung adenocarcinoma and tracked tumor evolution from single-transformed cells to metastatic tumors at unprecedented resolution. We found that the loss of the initial, stable alveolar-type2-like state was accompanied by a transient increase in plasticity. This was followed by the adoption of distinct transcriptional programs that enable rapid expansion and, ultimately, clonal sweep of stable subclones capable of metastasizing. Finally, tumors develop through stereotypical evolutionary trajectories, and perturbing additional tumor suppressors accelerates progression by creating novel trajectories. Our study elucidates the hierarchical nature of tumor evolution and, more broadly, enables in-depth studies of tumor progression.
    Keywords:  fitness; genetically engineered mouse model; lineage tracing; lung cancer; phylogenetics; plasticity; single cell; transcriptome heterogeneity; tumor evolution
    DOI:  https://doi.org/10.1016/j.cell.2022.04.015
  14. PLoS Comput Biol. 2022 May 02. 18(5): e1010059
    Protein degradation sets the fraction of active ribosomes at vanishing growth.
    Ludovico Calabrese, Jacopo Grilli, Matteo Osella, Christopher P Kempes, Marco Cosentino Lagomarsino, Luca Ciandrini.
      Growing cells adopt common basic strategies to achieve optimal resource allocation under limited resource availability. Our current understanding of such "growth laws" neglects degradation, assuming that it occurs slowly compared to the cell cycle duration. Here we argue that this assumption cannot hold at slow growth, leading to important consequences. We propose a simple framework showing that at slow growth protein degradation is balanced by a fraction of "maintenance" ribosomes. Consequently, active ribosomes do not drop to zero at vanishing growth, but as growth rate diminishes, an increasing fraction of active ribosomes performs maintenance. Through a detailed analysis of compiled data, we show that the predictions of this model agree with data from E. coli and S. cerevisiae. Intriguingly, we also find that protein degradation increases at slow growth, which we interpret as a consequence of active waste management and/or recycling. Our results highlight protein turnover as an underrated factor for our understanding of growth laws across kingdoms.
    DOI:  https://doi.org/10.1371/journal.pcbi.1010059
  15. Sci Rep. 2022 May 04. 12(1): 7300
    Short term treatment with a cocktail of rapamycin, acarbose and phenylbutyrate delays aging phenotypes in mice.
    Zhou Jiang, Juan Wang, Denise Imai, Tim Snider, Jenna Klug, Ruby Mangalindan, John Morton, Lida Zhu, Adam B Salmon, Jackson Wezeman, Jiayi Hu, Vinal Menon, Nicholas Marka, Laura Neidernhofer, Warren Ladiges.
      Pharmaceutical intervention of aging requires targeting multiple pathways, thus there is rationale to test combinations of drugs targeting different but overlapping processes. In order to determine if combining drugs shown to extend lifespan and healthy aging in mice would have greater impact than any individual drug, a cocktail diet containing 14 ppm rapamycin, 1000 ppm acarbose, and 1000 ppm phenylbutyrate was fed to 20-month-old C57BL/6 and HET3 4-way cross mice of both sexes for three months. Mice treated with the cocktail showed a sex and strain-dependent phenotype consistent with healthy aging including decreased body fat, improved cognition, increased strength and endurance, and decreased age-related pathology compared to mice treated with individual drugs or control. The severity of age-related lesions in heart, lungs, liver, and kidney was consistently decreased in mice treated with the cocktail compared to mice treated with individual drugs or control, suggesting an interactive advantage of the three drugs. This study shows that a combination of three drugs, each previously shown to enhance lifespan and health span in mice, is able to delay aging phenotypes in middle-aged mice more effectively than any individual drug in the cocktail over a 3-month treatment period.
    DOI:  https://doi.org/10.1038/s41598-022-11229-1
  16. Mol Cell Proteomics. 2022 May 02. pii: S1535-9476(22)00048-2. [Epub ahead of print] 100240
    eEF2K activity determines synergy to co-treatment of cancer cells with PI3K and MEK inhibitors.
    Maruan Hijazi, Pedro Casado, Nosheen Akhtar, Saul Alvarez-Teijeiro, Vinothini Rajeeve, Pedro R Cutillas.
      PI3K-mTOR and MEK/MAPK are the most frequently dysregulated signaling pathways in cancer. A problem that limits the success of therapies that target individual PI3K-MAPK members is that these pathways converge to regulate downstream functions and often compensate each other, leading to drug resistance and transient responses to therapy. In order to overcome resistance, therapies based on co-treatments with PI3K/AKT and MEK/MAPK inhibitors are now being investigated in clinical trials but the mechanisms of sensitivity to co-treatment are not fully understood. Using LC-MS/MS based phosphoproteomics, we found that eEF2K, a key convergence point downstream of MAPK and PI3K pathways, mediates synergism to co-treatment with trametinib plus pictilisib (which target MEK1/2 and PI3Kα/δ, respectively). Inhibition of eEF2K by siRNA or with a small molecule inhibitor reversed the anti-proliferative effects of the co-treatment with PI3K plus MEK inhibitors in a cell model specific manner. Systematic analysis in 12 acute myeloid leukemia (AML) cell lines revealed that eEF2K activity was increased in cells for which PI3K plus MEKi co-treatment is synergistic, while PKC potentially mediated resistance to such co-treatment. Together, our study uncovers eEF2K activity as a key mediator of responses to PI3Ki plus MEKi and as a potential biomarker to predict synergy to co-treatment in cancer cells.
    Keywords:  AML; biomarkers; cancer; combination therapy; eEF2K; kinase activity; phosphoproteomics; synergy
    DOI:  https://doi.org/10.1016/j.mcpro.2022.100240
  17. Science. 2022 May 05. e
    Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice.
    Victoria Acosta-Rodríguez, Filipa Rijo-Ferreira, Mariko Izumo, Pin Xu, Mary Wight-Carter, Carla B Green, Joseph S Takahashi.
      Caloric restriction (CR) prolongs lifespan, yet the mechanisms by which it does so remain poorly understood. Under CR, mice self-impose chronic cycles of 2-hour-feeding and 22-hour-fasting, raising the question whether calories, fasting, or time of day are causal. We show that 30%-CR is sufficient to extend lifespan 10%; however, a daily fasting interval and circadian-alignment of feeding act together to extend lifespan 35% in male C57BL/6J mice. These effects are independent of body weight. Aging induces widespread increases in gene expression associated with inflammation and decreases in expression of genes encoding components of metabolic pathways in liver from ad lib fed mice. CR at night ameliorates these aging-related changes. Thus, circadian interventions promote longevity and provide a perspective to further explore mechanisms of aging.
    DOI:  https://doi.org/10.1126/science.abk0297
  18. Nat Commun. 2022 May 03. 13(1): 2412
    Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism.
    Yunpeng Huang, Zhihui Wan, Yinglu Tang, Junxuan Xu, Bretton Laboret, Sree Nallamothu, Chenyu Yang, Boxiang Liu, Rongze Olivia Lu, Bingwei Lu, Juan Feng, Jing Cao, Susan Hayflick, Zhihao Wu, Bing Zhou.
      Human neurodegenerative disorders often exhibit similar pathologies, suggesting a shared aetiology. Key pathological features of Parkinson's disease (PD) are also observed in other neurodegenerative diseases. Pantothenate Kinase-Associated Neurodegeneration (PKAN) is caused by mutations in the human PANK2 gene, which catalyzes the initial step of de novo CoA synthesis. Here, we show that fumble (fbl), the human PANK2 homolog in Drosophila, interacts with PINK1 genetically. fbl and PINK1 mutants display similar mitochondrial abnormalities, and overexpression of mitochondrial Fbl rescues PINK1 loss-of-function (LOF) defects. Dietary vitamin B5 derivatives effectively rescue CoA/acetyl-CoA levels and mitochondrial function, reversing the PINK1 deficiency phenotype. Mechanistically, Fbl regulates Ref(2)P (p62/SQSTM1 homolog) by acetylation to promote mitophagy, whereas PINK1 regulates fbl translation by anchoring mRNA molecules to the outer mitochondrial membrane. In conclusion, Fbl (or PANK2) acts downstream of PINK1, regulating CoA/acetyl-CoA metabolism to promote mitophagy, uncovering a potential therapeutic intervention strategy in PD treatment.
    DOI:  https://doi.org/10.1038/s41467-022-30178-x
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