Functional Profiling Identifies Determinants of Arsenic Trioxide Cellular Toxicity

Abstract Arsenic exposure is a worldwide health concern associated with an increased risk of skin, lung, and bladder cancer but arsenic trioxide (AsIII) is also an effective chemotherapeutic agent. The current use of AsIII in chemotherapy is limited to acute promyelocytic leukemia (APL). However, As...

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Veröffentlicht in:Toxicological sciences 2019-05, Vol.169 (1), p.108-121
Hauptverfasser: Sobh, Amin, Loguinov, Alex, Yazici, Gulce Naz, Zeidan, Rola S, Tagmount, Abderrahmane, Hejazi, Nima S, Hubbard, Alan E, Zhang, Luoping, Vulpe, Chris D
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container_end_page 121
container_issue 1
container_start_page 108
container_title Toxicological sciences
container_volume 169
creator Sobh, Amin
Loguinov, Alex
Yazici, Gulce Naz
Zeidan, Rola S
Tagmount, Abderrahmane
Hejazi, Nima S
Hubbard, Alan E
Zhang, Luoping
Vulpe, Chris D
description Abstract Arsenic exposure is a worldwide health concern associated with an increased risk of skin, lung, and bladder cancer but arsenic trioxide (AsIII) is also an effective chemotherapeutic agent. The current use of AsIII in chemotherapy is limited to acute promyelocytic leukemia (APL). However, AsIII was suggested as a potential therapy for other cancer types including chronic myeloid leukemia (CML), especially when combined with other drugs. Here, we carried out a genome-wide CRISPR-based approach to identify modulators of AsIII toxicity in K562, a human CML cell line. We found that disruption of KEAP1, the inhibitory partner of the key antioxidant transcription factor Nrf2, or TXNDC17, a thioredoxin-like protein, markedly increased AsIII tolerance. Loss of the water channel AQP3, the zinc transporter ZNT1 and its regulator MTF1 also enhanced tolerance to AsIII whereas loss of the multidrug resistance protein ABCC1 increased sensitivity to AsIII. Remarkably, disruption of any of multiple genes, EEFSEC, SECISBP2, SEPHS2, SEPSECS, and PSTK, encoding proteins involved in selenocysteine metabolism increased resistance to AsIII. Our data suggest a model in which an intracellular interaction between selenium and AsIII may impact intracellular AsIII levels and toxicity. Together this work revealed a suite of cellular components/processes which modulate the toxicity of AsIII in CML cells. Targeting such processes simultaneously with AsIII treatment could potentiate AsIII in CML therapy.
doi_str_mv 10.1093/toxsci/kfz024
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The current use of AsIII in chemotherapy is limited to acute promyelocytic leukemia (APL). However, AsIII was suggested as a potential therapy for other cancer types including chronic myeloid leukemia (CML), especially when combined with other drugs. Here, we carried out a genome-wide CRISPR-based approach to identify modulators of AsIII toxicity in K562, a human CML cell line. We found that disruption of KEAP1, the inhibitory partner of the key antioxidant transcription factor Nrf2, or TXNDC17, a thioredoxin-like protein, markedly increased AsIII tolerance. Loss of the water channel AQP3, the zinc transporter ZNT1 and its regulator MTF1 also enhanced tolerance to AsIII whereas loss of the multidrug resistance protein ABCC1 increased sensitivity to AsIII. Remarkably, disruption of any of multiple genes, EEFSEC, SECISBP2, SEPHS2, SEPSECS, and PSTK, encoding proteins involved in selenocysteine metabolism increased resistance to AsIII. Our data suggest a model in which an intracellular interaction between selenium and AsIII may impact intracellular AsIII levels and toxicity. Together this work revealed a suite of cellular components/processes which modulate the toxicity of AsIII in CML cells. Targeting such processes simultaneously with AsIII treatment could potentiate AsIII in CML therapy.</description><identifier>ISSN: 1096-6080</identifier><identifier>EISSN: 1096-0929</identifier><identifier>DOI: 10.1093/toxsci/kfz024</identifier><identifier>PMID: 30815697</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>Antineoplastic Agents - pharmacology ; Arsenic Trioxide - pharmacology ; Cell Survival - drug effects ; CRISPR-Cas Systems ; Dose-Response Relationship, Drug ; Functional Profiling of Arsenic Trioxide ; Gene Editing ; Gene Expression Profiling ; Gene Expression Regulation, Leukemic ; HEK293 Cells ; Humans ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology ; Signal Transduction ; Sodium Selenite - pharmacology ; Time Factors ; Transcriptome</subject><ispartof>Toxicological sciences, 2019-05, Vol.169 (1), p.108-121</ispartof><rights>The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com 2019</rights><rights>The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. 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Our data suggest a model in which an intracellular interaction between selenium and AsIII may impact intracellular AsIII levels and toxicity. Together this work revealed a suite of cellular components/processes which modulate the toxicity of AsIII in CML cells. Targeting such processes simultaneously with AsIII treatment could potentiate AsIII in CML therapy.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Arsenic Trioxide - pharmacology</subject><subject>Cell Survival - drug effects</subject><subject>CRISPR-Cas Systems</subject><subject>Dose-Response Relationship, Drug</subject><subject>Functional Profiling of Arsenic Trioxide</subject><subject>Gene Editing</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Leukemic</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>K562 Cells</subject><subject>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy</subject><subject>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics</subject><subject>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism</subject><subject>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology</subject><subject>Signal Transduction</subject><subject>Sodium Selenite - pharmacology</subject><subject>Time Factors</subject><subject>Transcriptome</subject><issn>1096-6080</issn><issn>1096-0929</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUblOxDAQtRCIu6RFKWkC4zjr2A0SWk4JCYSW2nKcMRiy9mInaOHrCdrlqqjmenpvZh4hexQOKUh21IV5Mu7o2b5DUa6QzaHJc5CFXF3mHARskK2UngAo5SDXyQYDQUdcVpvk7rz3pnPB6za7jcG61vmH7KpB3znrMGWn2GGcOq99l7Jgs5OY0DuTTaILc9dgNsa27Vsds8lQG9e97ZA1q9uEu8u4Te7Pzybjy_z65uJqfHKdm1LwLrecSitYzZi0CLYeFWAkBc2lFrouRoC15vXQrxohRljVKKTljYaiAo2MsW1yvOCd9fUUGzOsHHWrZtFNdXxTQTv1d-Ldo3oIr4qXohSiHAgOlgQxvPSYOjV1yQznaI-hT6qgogLGaFEN0HwBNTGkFNF-y1BQnz6ohQ9q4cOA3_-92zf66_E_2qGf_cP1AXWelvE</recordid><startdate>20190501</startdate><enddate>20190501</enddate><creator>Sobh, Amin</creator><creator>Loguinov, Alex</creator><creator>Yazici, Gulce Naz</creator><creator>Zeidan, Rola S</creator><creator>Tagmount, Abderrahmane</creator><creator>Hejazi, Nima S</creator><creator>Hubbard, Alan E</creator><creator>Zhang, Luoping</creator><creator>Vulpe, Chris D</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20190501</creationdate><title>Functional Profiling Identifies Determinants of Arsenic Trioxide Cellular Toxicity</title><author>Sobh, Amin ; 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The current use of AsIII in chemotherapy is limited to acute promyelocytic leukemia (APL). However, AsIII was suggested as a potential therapy for other cancer types including chronic myeloid leukemia (CML), especially when combined with other drugs. Here, we carried out a genome-wide CRISPR-based approach to identify modulators of AsIII toxicity in K562, a human CML cell line. We found that disruption of KEAP1, the inhibitory partner of the key antioxidant transcription factor Nrf2, or TXNDC17, a thioredoxin-like protein, markedly increased AsIII tolerance. Loss of the water channel AQP3, the zinc transporter ZNT1 and its regulator MTF1 also enhanced tolerance to AsIII whereas loss of the multidrug resistance protein ABCC1 increased sensitivity to AsIII. Remarkably, disruption of any of multiple genes, EEFSEC, SECISBP2, SEPHS2, SEPSECS, and PSTK, encoding proteins involved in selenocysteine metabolism increased resistance to AsIII. Our data suggest a model in which an intracellular interaction between selenium and AsIII may impact intracellular AsIII levels and toxicity. Together this work revealed a suite of cellular components/processes which modulate the toxicity of AsIII in CML cells. Targeting such processes simultaneously with AsIII treatment could potentiate AsIII in CML therapy.</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>30815697</pmid><doi>10.1093/toxsci/kfz024</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record>
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subjects Antineoplastic Agents - pharmacology
Arsenic Trioxide - pharmacology
Cell Survival - drug effects
CRISPR-Cas Systems
Dose-Response Relationship, Drug
Functional Profiling of Arsenic Trioxide
Gene Editing
Gene Expression Profiling
Gene Expression Regulation, Leukemic
HEK293 Cells
Humans
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology
Signal Transduction
Sodium Selenite - pharmacology
Time Factors
Transcriptome
title Functional Profiling Identifies Determinants of Arsenic Trioxide Cellular Toxicity
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