Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion.

Abstract:

:Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.

authors

Elliott IA,Dann AM,Xu S,Kim SS,Abt ER,Kim W,Poddar S,Moore A,Zhou L,Williams JL,Capri JR,Ghukasyan R,Matsumura C,Tucker DA,Armstrong WR,Cabebe AE,Wu N,Li L,Le TM,Radu CG,Donahue TR

doi

10.1073/pnas.1812410116

subject

Has Abstract

pub_date

2019-04-02 00:00:00

pages

6842-6847

issue

14

eissn

0027-8424

issn

1091-6490

pii

1812410116

journal_volume

116

pub_type

杂志文章
  • The impact of the certainty context on the process of choice.

    abstract::In this study we examine how the introduction of a reference lottery with nonrandom outcomes alters the way in which choices among pairs of lotteries are made, even if it does not alter the choices. We use different domains (some of the lotteries produce gains, other losses) and different contexts (one member of the p...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0530279100

    authors: Dickhaut J,McCabe K,Nagode JC,Rustichini A,Smith K,Pardo JV

    更新日期:2003-03-18 00:00:00

  • Definition of a physiologic aging autoantigen by using synthetic peptides of membrane protein band 3: localization of the active antigenic sites.

    abstract::Senescent cell antigen (SCA), an aging antigen, is a protein that appears on old cells and marks them for removal by the immune system in mammals. It is derived from band 3, a ubiquitous membrane transport protein found in diverse cell types and tissues. We have used synthetic peptides to identify aging antigenic site...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.87.15.5734

    authors: Kay MM,Marchalonis JJ,Hughes J,Watanabe K,Schluter SF

    更新日期:1990-08-01 00:00:00

  • Indirubin derivatives inhibit Stat3 signaling and induce apoptosis in human cancer cells.

    abstract::Stat3 protein has an important role in oncogenesis and is a promising anticancer target. Indirubin, the active component of a traditional Chinese herbal medicine, has been shown previously to inhibit cyclin-dependent kinases, resulting in cell cycle arrest. Here, we show that the indirubin derivatives E564, E728, and ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0409467102

    authors: Nam S,Buettner R,Turkson J,Kim D,Cheng JQ,Muehlbeyer S,Hippe F,Vatter S,Merz KH,Eisenbrand G,Jove R

    更新日期:2005-04-26 00:00:00

  • High-pressure transformations in xenon hydrates.

    abstract::A high-pressure investigation of the Xe*H(2)O chemical system was conducted by using diamond-anvil cell techniques combined with in situ Raman spectroscopy, synchrotron x-ray diffraction, and laser heating. Structure I xenon clathrate was observed to be stable up to 1.8 GPa, at which pressure it transforms to a new Xe...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.221602698

    authors: Sanloup C,Mao Hk HK,Hemley RJ

    更新日期:2002-01-08 00:00:00

  • Improved protein structure prediction using predicted interresidue orientations.

    abstract::The prediction of interresidue contacts and distances from coevolutionary data using deep learning has considerably advanced protein structure prediction. Here, we build on these advances by developing a deep residual network for predicting interresidue orientations, in addition to distances, and a Rosetta-constrained...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1914677117

    authors: Yang J,Anishchenko I,Park H,Peng Z,Ovchinnikov S,Baker D

    更新日期:2020-01-21 00:00:00

  • Complement activation by isolated myelin: activation of the classical pathway in the absence of myelin-specific antibodies.

    abstract::Many pathological conditions of the central nervous system involve damage to and removal of myelin membrane. Very little is known about initiation of this membrane damage and the mechanisms of disposal of the damaged tissue. We are interested in the interaction between complement (the components of complement are desi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.79.10.3290

    authors: Vanguri P,Koski CL,Silverman B,Shin ML

    更新日期:1982-05-01 00:00:00

  • Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations.

    abstract::Factor XI (plasma thromboplastin antecedent) deficiency is a blood coagulation abnormality occurring in high frequency in Ashkenazi Jews. Three independent point mutations that result in a blood coagulation abnormality have been identified in the factor XI gene of six unrelated Ashkenazi patients. These mutations eith...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.20.7667

    authors: Asakai R,Chung DW,Ratnoff OD,Davie EW

    更新日期:1989-10-01 00:00:00

  • Community-based conservation in a globalized world.

    abstract::Communities have an important role to play in biodiversity conservation. However, community-based conservation as a panacea, like government-based conservation as a panacea, ignores the necessity of managing commons at multiple levels, with vertical and horizontal interplay among institutions. The study of conservatio...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0702098104

    authors: Berkes F

    更新日期:2007-09-25 00:00:00

  • TMEM59 potentiates Wnt signaling by promoting signalosome formation.

    abstract::Wnt/β-catenin signaling controls development and adult tissue homeostasis by regulating cell proliferation and cell fate decisions. Wnt binding to its receptors Frizzled (FZD) and low-density lipoprotein-related 6 (LRP6) at the cell surface initiates a signaling cascade that leads to the transcription of Wnt target ge...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1721321115

    authors: Gerlach JP,Jordens I,Tauriello DVF,van 't Land-Kuper I,Bugter JM,Noordstra I,van der Kooij J,Low TY,Pimentel-Muiños FX,Xanthakis D,Fenderico N,Rabouille C,Heck AJR,Egan DA,Maurice MM

    更新日期:2018-04-24 00:00:00

  • Intrinsic and extrinsic contributions to stochasticity in gene expression.

    abstract::Gene expression is a stochastic, or "noisy," process. This noise comes about in two ways. The inherent stochasticity of biochemical processes such as transcription and translation generates "intrinsic" noise. In addition, fluctuations in the amounts or states of other cellular components lead indirectly to variation i...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.162041399

    authors: Swain PS,Elowitz MB,Siggia ED

    更新日期:2002-10-01 00:00:00

  • Role of loop-helix interactions in stabilizing four-helix bundle proteins.

    abstract::One of the critical issues regarding proteins with a four-helix bundle motif is which interactions play the major role in stabilizing this type of folded structure: the interaction among the four alpha-helices or the interaction between the loop and helix segments. To answer this question, an energetic analysis has be...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.89.16.7315

    authors: Chou KC,Maggiora GM,Scheraga HA

    更新日期:1992-08-15 00:00:00

  • Inhibition of RNA polymerase II transcription in human cells by synthetic DNA-binding ligands.

    abstract::Sequence-specific DNA-binding small molecules that can permeate human cells potentially could regulate transcription of specific genes. Multiple cellular DNA-binding transcription factors are required by HIV type 1 for RNA synthesis. Two pyrrole-imidazole polyamides were designed to bind DNA sequences immediately adja...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.22.12890

    authors: Dickinson LA,Gulizia RJ,Trauger JW,Baird EE,Mosier DE,Gottesfeld JM,Dervan PB

    更新日期:1998-10-27 00:00:00

  • Condition and fate of logged forests in the Brazilian Amazon.

    abstract::The long-term viability of a forest industry in the Amazon region of Brazil depends on the maintenance of adequate timber volume and growth in healthy forests. Using extensive high-resolution satellite analyses, we studied the forest damage caused by recent logging operations and the likelihood that logged forests wou...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0604093103

    authors: Asner GP,Broadbent EN,Oliveira PJ,Keller M,Knapp DE,Silva JN

    更新日期:2006-08-22 00:00:00

  • Unusual calcium-activated potassium channels of bovine parathyroid cells.

    abstract::Parathyroid cells have unusual responses to an increase in the external calcium concentration--a reduction in secretion and a depolarization. In an attempt to explain this behavior, we have studied voltage-clamped inside-out patches from bovine parathyroid cells. We found a potassium-selective channel that requires in...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.85.19.7236

    authors: Jia M,Ehrenstein G,Iwasa K

    更新日期:1988-10-01 00:00:00

  • Heterogeneity of long-history migration explains cultural differences in reports of emotional expressivity and the functions of smiles.

    abstract::A small number of facial expressions may be universal in that they are produced by the same basic affective states and recognized as such throughout the world. However, other aspects of emotionally expressive behavior vary widely across culture. Just why do they vary? We propose that some cultural differences in expre...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1413661112

    authors: Rychlowska M,Miyamoto Y,Matsumoto D,Hess U,Gilboa-Schechtman E,Kamble S,Muluk H,Masuda T,Niedenthal PM

    更新日期:2015-05-12 00:00:00

  • Single-molecule FRET studies on the cotranscriptional folding of a thiamine pyrophosphate riboswitch.

    abstract::Because RNAs fold as they are being synthesized, their transcription rate can affect their folding. Here, we report the results of single-molecule fluorescence studies that characterize the ligand-dependent cotranscriptional folding of the Escherichia coli thiM riboswitch that regulates translation. We found that the ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1712983115

    authors: Uhm H,Kang W,Ha KS,Kang C,Hohng S

    更新日期:2018-01-09 00:00:00

  • Selective alkylation of carcinogenic 9-anthryloxirane at the N-3 position of adenine in DNA.

    abstract::Carcinogenic 9-anthryloxirane binds covalently to calf thymus DNA and poly(dA-dT). Application of the technique for DNA sequence determination shows that acid cleavage of the modified DNA frees approximately half of the anthryl groups from the DNA. HPLC analysis indicates that an adenine adduct and the glycol derived ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.82.16.5250

    authors: Yang NC,Chang CW

    更新日期:1985-08-01 00:00:00

  • Transcription terminates near the poly(A) site in the CYC1 gene of the yeast Saccharomyces cerevisiae.

    abstract::A 38-base-pair region required for normal CYC1 mRNA 3' end formation in Saccharomyces cerevisiae was shown to be necessary for the termination of transcription in vivo by examining the stability of CEN3 plasmids. CEN3 plasmids were stably maintained during vegetative growth, unless a GAL1 transcript impinged on the CE...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.21.8348

    authors: Russo P,Sherman F

    更新日期:1989-11-01 00:00:00

  • Dual-targeted tRNA-dependent amidotransferase ensures both mitochondrial and chloroplastic Gln-tRNAGln synthesis in plants.

    abstract::Aminoacyl-tRNAs are generally formed by direct attachment of an amino acid to tRNAs by aminoacyl-tRNA synthetases, but Gln-tRNA is an exception to this rule. Gln-tRNA(Gln) is formed by this direct pathway in the eukaryotic cytosol and in protists or fungi mitochondria but is formed by an indirect transamidation pathwa...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0712299105

    authors: Pujol C,Bailly M,Kern D,Maréchal-Drouard L,Becker H,Duchêne AM

    更新日期:2008-04-29 00:00:00

  • Pex1, a pollen-specific gene with an extensin-like domain.

    abstract::We report here the identification of a pollen-specific gene from Zea mays that contains multiple Ser-(Pro)n repeats, the motif found in the cell wall-associated extensins. Sequence analysis reveals that the encoded protein has a putative globular domain at the N terminus and an extensin-like domain at the C terminus. ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.8.3086

    authors: Rubinstein AL,Broadwater AH,Lowrey KB,Bedinger PA

    更新日期:1995-04-11 00:00:00

  • Dystrophin protects the sarcolemma from stresses developed during muscle contraction.

    abstract::The protein dystrophin, normally found on the cytoplasmic surface of skeletal muscle cell membranes, is absent in patients with Duchenne muscular dystrophy as well as mdx (X-linked muscular dystrophy) mice. Although its primary structure has been determined, the precise functional role of dystrophin remains the subjec...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.90.8.3710

    authors: Petrof BJ,Shrager JB,Stedman HH,Kelly AM,Sweeney HL

    更新日期:1993-04-15 00:00:00

  • roundabout4 is essential for angiogenesis in vivo.

    abstract::Stereotypical patterns of vascular and neuronal networks suggest that specific genetic programs tightly control path determination and, consequently, angiogenesis and axon-guidance mechanisms. Our study focuses on one member of the roundabout family of receptors, which traditionally mediate repulsion from the midline....

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0408318102

    authors: Bedell VM,Yeo SY,Park KW,Chung J,Seth P,Shivalingappa V,Zhao J,Obara T,Sukhatme VP,Drummond IA,Li DY,Ramchandran R

    更新日期:2005-05-03 00:00:00

  • 5'-CGA sequence is a strong motif for homo base-paired parallel-stranded DNA duplex as revealed by NMR analysis.

    abstract::The structure of the non-self-complementary DNA heptamer d(CGACGAC) at low pH has been determined by the quantitative NMR refinement procedure designated SPEDREF (SPEctral-Driven REFinement). Acid-base titration of the molecule indicated a prominent n = 2 pKa near 6.8. In the pH range up to 6.0, the heptamer forms a r...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.90.11.5224

    authors: Robinson H,Wang AH

    更新日期:1993-06-01 00:00:00

  • Memory loss in a nonnavigational spatial task after hippocampal inactivation in monkeys.

    abstract::The hippocampus has a well-documented role for spatial navigation across species, but its role for spatial memory in nonnavigational tasks is uncertain. In particular, when monkeys are tested in tasks that do not require navigation, spatial memory seems unaffected by lesions of the hippocampus. However, the interpreta...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1320562111

    authors: Forcelli PA,Palchik G,Leath T,DesJardin JT,Gale K,Malkova L

    更新日期:2014-03-18 00:00:00

  • Statistics of natural reverberation enable perceptual separation of sound and space.

    abstract::In everyday listening, sound reaches our ears directly from a source as well as indirectly via reflections known as reverberation. Reverberation profoundly distorts the sound from a source, yet humans can both identify sound sources and distinguish environments from the resulting sound, via mechanisms that remain uncl...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1612524113

    authors: Traer J,McDermott JH

    更新日期:2016-11-29 00:00:00

  • Molecular cloning of the human T-lymphocyte surface CD2 (T11) antigen.

    abstract::CD2 (T11, sheep erythrocyte receptor) is a surface antigen of the human T-lymphocyte lineage. cDNA clones encoding CD2 have been isolated by using the purified, denatured CD2 to raise a rat antiserum. Positive clones were recognized in a phage lambda gt11 expression library prepared from the human leukemia T-cell line...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.83.22.8718

    authors: Sewell WA,Brown MH,Dunne J,Owen MJ,Crumpton MJ

    更新日期:1986-11-01 00:00:00

  • Transcriptional regulation of the tyrosine hydroxylase gene by glucocorticoid and cyclic AMP.

    abstract::Glucocorticoid and cyclic AMP increase tyrosine hydroxylase (TH) activity and mRNA levels in pheochromocytoma cultures. The transcriptional activity of the TH gene, as measured by nuclear run-on assay, is also increased when cultures are treated with the synthetic glucocorticoid dexamethasone or agents that increase i...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.84.11.3550

    authors: Lewis EJ,Harrington CA,Chikaraishi DM

    更新日期:1987-06-01 00:00:00

  • Understanding, predicting, and tuning the fragility of vitrimeric polymers.

    abstract::Fragility is an empirical property that describes how abruptly a glass-forming material solidifies upon supercooling. The degree of fragility carries important implications for the functionality and processability of a material, as well as for our fundamental understanding of the glass transition. However, the microst...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1912571116

    authors: Ciarella S,Biezemans RA,Janssen LMC

    更新日期:2019-12-10 00:00:00

  • Identification of a nuclear domain with deacetylase activity.

    abstract::Here, we describe the identification and characterization of a nuclear body (matrix-associated deacetylase body) whose formation and integrity depend on deacetylase activity. Typically, there are 20-40 0.5-microM bodies per nucleus, although the size and number can vary substantially. The structure appears to contain ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.97.19.10330

    authors: Downes M,Ordentlich P,Kao HY,Alvarez JG,Evans RM

    更新日期:2000-09-12 00:00:00

  • Isolation and characterization of a temperature-sensitive mutant of avian myeloblastosis virus.

    abstract::A temperature-sensitive (ts) mutant, GA 907/7, was isolated after mutagen treatment of avian myeloblastosis virus. When bone marrow cells or secondary yolk sac macrophages were infected with GA 907/7, the expression of transformation was greatly reduced at 41 degrees C. The results of temperature-shift experiments sug...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.80.5.1421

    authors: Moscovici MG,Moscovici C

    更新日期:1983-03-01 00:00:00