Functional Profiling Identifies Determinants of Arsenic Trioxide Cellular Toxicity

Toxicological Sciences : an Official Journal of the Society of Toxicology
Amin SobhChris D Vulpe

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 intracellu...Continue Reading

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Citations

Feb 28, 2020·Toxicological Sciences : an Official Journal of the Society of Toxicology·Henry LujanChristie Sayes
Dec 24, 2020·Small·Ellen FritscheKatharina Koch
May 28, 2021·Current Protocols·Amin SobhChristopher D Vulpe
Nov 2, 2021·The Journal of Toxicological Sciences·Nivedita Chatterjee, Xiaowei Zhang

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