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Toxicol Sci. 2019 Jan 25. pii: kfz024. doi: 10.1093/toxsci/kfz024. [Epub ahead of print]

Functional profiling identifies determinants of arsenic trioxide cellular toxicity.

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Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida.
Department of Nutritional Science & Toxicology, Comparative Biochemistry Program, University of California, Berkeley.
Department of Histology and Embryology, Faculty of medicine, Erzincan Binali Yildirim University, Erzincan, Turkey.
Division of Biostatistics and Epidemiology, School of Public Health, University of California, Berkeley.
Center for Computational Biology, University of California, Berkeley.
Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley.


Arsenic exposure is a worldwide health concern associated with an increased risk of skin, lung and bladder cancer but arsenic trioxide (ATO; 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 transcriptional factor Nrf2, or TXNDC17, a thioredoxin-like protein markedly increased AsIII tolerance. Loss of aquaporin 3 (AQP3), the zinc transporter ZNT1 (SLC30A1) and its regulator metal regulatory transcription factor 1 (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, 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.


Arsenic; CRISPR screen; selenium; selenocysteine


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