bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2020–08–16
seven papers selected by
Ralitsa Radostinova Madsen, University College London
  1. Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer.
  2. Small Extracellular Vesicle Regulation of Mitochondrial Dynamics Reprograms a Hypoxic Tumor Microenvironment.
  3. Endothelial dysfunction due to selective insulin resistance in vascular endothelium: insights from mechanistic modeling.
  4. Lipid Exchangers: Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism.
  5. Mechanism of PRL2 phosphatase-mediated PTEN degradation and tumorigenesis.
  6. Regulation of colonic epithelial cell homeostasis by mTORC1.
  7. Sodium glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks.
  1. Breast Cancer Res. 2020 Aug 14. 22(1): 89
    Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer.
    Neil A O'Brien, Martina S J McDermott, Dylan Conklin, Tong Luo, Raul Ayala, Suruchi Salgar, Kevin Chau, Emmanuelle DiTomaso, Naveen Babbar, Faye Su, Alex Gaither, Sara A Hurvitz, Ronald Linnartz, Kristine Rose, Samit Hirawat, Dennis J Slamon.
       BACKGROUND: Combined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2- breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance.
    METHODS: In this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance.
    RESULTS: We show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2- breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2- breast cancer models.
    CONCLUSIONS: These data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2- breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.
    Keywords:  Alpelisib; Palbociclib; Translational
    DOI:  https://doi.org/10.1186/s13058-020-01320-8
  2. Dev Cell. 2020 Aug 04. pii: S1534-5807(20)30588-8. [Epub ahead of print]
    Small Extracellular Vesicle Regulation of Mitochondrial Dynamics Reprograms a Hypoxic Tumor Microenvironment.
    Irene Bertolini, Jagadish C Ghosh, Andrew V Kossenkov, Sudheer Mulugu, Shiv Ram Krishn, Valentina Vaira, Jun Qin, Edward F Plow, Lucia R Languino, Dario C Altieri.
      The crosstalk between tumor cells and the adjacent normal epithelium contributes to cancer progression, but its regulators have remained elusive. Here, we show that breast cancer cells maintained in hypoxia release small extracellular vesicles (sEVs) that activate mitochondrial dynamics, stimulate mitochondrial movements, and promote organelle accumulation at the cortical cytoskeleton in normal mammary epithelial cells. This results in AKT serine/threonine kinase (Akt) activation, membrane focal adhesion turnover, and increased epithelial cell migration. RNA sequencing profiling identified integrin-linked kinase (ILK) as the most upregulated pathway in sEV-treated epithelial cells, and genetic or pharmacologic targeting of ILK reversed mitochondrial reprogramming and suppressed sEV-induced cell movements. In a three-dimensional (3D) model of mammary gland morphogenesis, sEV treatment induced hallmarks of malignant transformation, with deregulated cell death and/or cell proliferation, loss of apical-basal polarity, and appearance of epithelial-to-mesenchymal transition (EMT) markers. Therefore, sEVs released by hypoxic breast cancer cells reprogram mitochondrial dynamics and induce oncogenic changes in a normal mammary epithelium.
    Keywords:  breast cancer; extracellular vesicles; hypoxia; mitochondria; morphogenesis; normal mammary epithelium; transformation
    DOI:  https://doi.org/10.1016/j.devcel.2020.07.014
  3. Am J Physiol Endocrinol Metab. 2020 Aug 10.
    Endothelial dysfunction due to selective insulin resistance in vascular endothelium: insights from mechanistic modeling.
    Ranganath Muniyappa, Hui Chen, Monica Montagnani, Arthur Sherman, Michael J Quon.
      Previously, we have used mathematical modeling to gain mechanistic insight into insulin-stimulated glucose uptake. Phosphatidylinositol 3-kinase-dependent (PI3K) insulin signaling required for metabolic actions of insulin also regulates endothelium-dependent production of the vasodilator nitric oxide (NO). Vasodilation increases blood flow that augments direct metabolic actions of insulin in skeletal muscle. This is counterbalanced by mitogen-activated protein kinase (MAPK)-dependent insulin signaling in endothelium that promotes secretion of the vasoconstrictor endothelin-1 (ET-1). In the present study, we extended our model of metabolic insulin signaling into a dynamic model of insulin signaling in vascular endothelium that explicitly represents opposing PI3K/NO and MAPK/ET-1 pathways. Novel NO and ET-1 subsystems were developed using published and new experimental data to generate model structures/parameters. The signal-response relationships of our model with respect to insulin-stimulated NO production, ET-1 secretion, and resultant vascular tone, agree with published experimental data independent of those used for model development. Simulations of pathological stimuli directly impairing only insulin-stimulated PI3K/Akt activity predict altered dynamics of NO and ET-1 consistent with endothelial dysfunction in insulin-resistant states. Indeed, modeling pathway-selective impairment of PI3K/Akt pathways consistent with insulin resistance caused by glucotoxicity, lipotoxicity, or inflammation predict diminished NO production and increased ET-1 secretion characteristic of diabetes and endothelial dysfunction. We conclude that our mathematical model of insulin signaling in vascular endothelium supports the hypothesis that pathway-selective insulin resistance accounts, in part, for relationships between insulin resistance and endothelial dysfunction. This may be relevant for developing novel approaches for treatment of diabetes and its cardiovascular complications.
    Keywords:  Endothelin-1; Endothelium; Insulin signaling; Mathematical modeling; Nitric oxide
    DOI:  https://doi.org/10.1152/ajpendo.00247.2020
  4. Front Cell Dev Biol. 2020 ;8 663
    Lipid Exchangers: Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism.
    Nicolas-Frédéric Lipp, Souade Ikhlef, Julie Milanini, Guillaume Drin.
      Lipids are amphiphilic molecules that self-assemble to form biological membranes. Thousands of lipid species coexist in the cell and, once combined, define organelle identity. Due to recent progress in lipidomic analysis, we now know how lipid composition is finely tuned in different subcellular regions. Along with lipid synthesis, remodeling and flip-flop, lipid transfer is one of the active processes that regulates this intracellular lipid distribution. It is mediated by Lipid Transfer Proteins (LTPs) that precisely move certain lipid species across the cytosol and between the organelles. A particular subset of LTPs from three families (Sec14, PITP, OSBP/ORP/Osh) act as lipid exchangers. A striking feature of these exchangers is that they use phosphatidylinositol or phosphoinositides (PIPs) as a lipid ligand and thereby have specific links with PIP metabolism and are thus able to both control the lipid composition of cellular membranes and their signaling capacity. As a result, they play pivotal roles in cellular processes such as vesicular trafficking and signal transduction at the plasma membrane. Recent data have shown that some PIPs are used as energy by lipid exchangers to generate lipid gradients between organelles. Here we describe the importance of lipid counter-exchange in the cell, its structural basis, and presumed links with pathologies.
    Keywords:  lipid exchange; lipid transfer proteins; membrane contact sites; phosphatidylserine; phosphoinositides; signaling; sterol; vesicular trafficking
    DOI:  https://doi.org/10.3389/fcell.2020.00663
  5. Proc Natl Acad Sci U S A. 2020 Aug 11. pii: 202002964. [Epub ahead of print]
    Mechanism of PRL2 phosphatase-mediated PTEN degradation and tumorigenesis.
    Qinglin Li, Yunpeng Bai, L Tiffany Lyle, Guimei Yu, Ovini Amarasinghe, Frederick Nguele Meke, Colin Carlock, Zhong-Yin Zhang.
      Tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) levels are frequently found reduced in human cancers, but how PTEN is down-regulated is not fully understood. In addition, although a compelling connection exists between PRL (phosphatase of regenerating liver) 2 and cancer, how this phosphatase induces oncogenesis has been an enigma. Here, we discovered that PRL2 ablation inhibits PTEN heterozygosity-induced tumorigenesis. PRL2 deficiency elevates PTEN and attenuates AKT signaling, leading to decreased proliferation and increased apoptosis in tumors. We also found that high PRL2 expression is correlated with low PTEN level with reduced overall patient survival. Mechanistically, we identified PTEN as a putative PRL2 substrate and demonstrated that PRL2 down-regulates PTEN by dephosphorylating PTEN at Y336, thereby augmenting NEDD4-mediated PTEN ubiquitination and proteasomal degradation. Given the strong cancer susceptibility to subtle reductions in PTEN, the ability of PRL2 to down-regulate PTEN provides a biochemical basis for its oncogenic propensity. The results also suggest that pharmacological targeting of PRL2 could provide a novel therapeutic strategy to restore PTEN, thereby obliterating PTEN deficiency-induced malignancies.
    Keywords:  NEDD4; PRL2; PTEN; protein tyrosine phosphatases; ubiquitination
    DOI:  https://doi.org/10.1073/pnas.2002964117
  6. Sci Rep. 2020 Aug 14. 10(1): 13810
    Regulation of colonic epithelial cell homeostasis by mTORC1.
    Takenori Kotani, Jajar Setiawan, Tasuku Konno, Noriko Ihara, Saki Okamoto, Yasuyuki Saito, Yoji Murata, Tetsuo Noda, Takashi Matozaki.
      Cell signaling important for homeostatic regulation of colonic epithelial cells (CECs) remains poorly understood. Mammalian target of rapamycin complex 1 (mTORC1), a protein complex that contains the serine-threonine kinase mTOR, mediates signaling that underlies the control of cellular functions such as proliferation and autophagy by various external stimuli. We here show that ablation of tuberous sclerosis complex 2 (Tsc2), a negative regulator of mTORC1, specifically in intestinal epithelial cells of mice resulted in increased activity of mTORC1 of, as well as increased proliferative activity of, CECs. Such Tsc2 ablation also reduced the population of Lgr5-positive colonic stem cells and the expression of Wnt target genes in CECs. The stimulatory phosphorylation of the kinase Akt and inhibitory phosphorylation of glycogen synthase kinase 3β were both markedly decreased in the colon of the Tsc2 conditional knockout (CKO) mice. Development of colonic organoids with cryptlike structures was enhanced for Tsc2 CKO mice compared with control mice. Finally, Tsc2 CKO mice manifested increased susceptibility to dextran sulfate sodium-induced colitis. Our results thus suggest that mTORC1 activity promotes the proliferation of, as well as the expression of Wnt target genes in, CECs and thereby contributes to colonic organogenesis and homeostasis.
    DOI:  https://doi.org/10.1038/s41598-020-70655-1
  7. J Biol Chem. 2020 Aug 12. pii: jbc.REV120.008387. [Epub ahead of print]
    Sodium glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks.
    Rachel J Perry, Gerald I Shulman.
      In a healthy person, the kidney filters nearly 200 g of glucose per day, almost all of which is reabsorbed. The primary transporter responsible for renal glucose reabsorption is sodium-glucose cotransporter-2 (SGLT2). Based on the impact of SGLT2 to prevent renal glucose wasting, SGLT2 inhibitors have been developed to treat diabetes and are the newest class of glucose-lowering agents approved in the U.S. By inhibiting glucose reabsorption in the proximal tubule, these agents promote glycosuria, thereby reducing blood glucose concentrations and often resulting in modest weight loss. Recent work in humans and rodents has demonstrated that the clinical utility of these agents may not be limited to diabetes management: SGLT2 inhibitors have also shown therapeutic promise in improving outcomes in heart failure, atrial fibrillation, and, in preclinical studies, certain cancers. Unfortunately, these benefits are not without risk: SGLT2 inhibitors predispose to euglycemic ketoacidosis in those with type 2 diabetes, and largely for this reason, are not approved to treat type 1 diabetes. The mechanism for each of the beneficial and the harmful effects of SGLT2 inhibitors - with the exception of their effect to lower plasma glucose concentrations - is an area of active investigation. In this review, we discuss the mechanisms by which these drugs cause euglycemic ketoacidosis, hyperglucagonemia and stimulate hepatic gluconeogenesis as well as their beneficial effects in cardiovascular disease and cancer. In so doing, we aim to highlight the crucial role for selecting patients for SGLT2 inhibitor therapy and highlight several crucial questions that remain unanswered.
    Keywords:  Type 1 diabetes; Type 2 diabetes; counter regulation; diabetes; euglycemic-ketoacidosis; glucagon; gluconeogenesis; insulinopenia; keto genesis; lipolysis
    DOI:  https://doi.org/10.1074/jbc.REV120.008387
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