Functional Profiling Identifies Determinants of Arsenic Trioxide Cellular Toxicity.

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Sobh A., Loguinov A., Yazici G. N., Zeidan R. S., Tagmount A., Hejazi N. S., ...Daha Fazla

Toxicological sciences : an official journal of the Society of Toxicology, cilt.169, sa.1, ss.108-121, 2019 (SCI-Expanded, Scopus)

Özet

Arsenic exposure is a worldwide health concern associated with an increased risk of skin, lung, and bladder cancer but arsenic trioxide (As-III) is also an effective chemotherapeutic agent. The current use of As-III in chemotherapy is limited to acute promyelocytic leukemia (APL). However, As-III 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 As-III 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 As-III tolerance. Loss of the water channel AQP3, the zinc transporter ZNT1 and its regulator MTF1 also enhanced tolerance to As-III whereas loss of the multidrug resistance protein ABCC1 increased sensitivity to As-III. Remarkably, disruption of any of multiple genes, EEFSEC, SECISBP2, SEPHS2, SEPSECS, and PSTK, encoding proteins involved in selenocysteine metabolismincreased resistance to As-III. Our data suggest a model in which an intracellular interaction between selenium and As-III may impact intracellular As-III levels and toxicity. Together this work revealed a suite of cellular components/processes which modulate the toxicity of As-III in CML cells. Targeting such processes simultaneously with As-III treatment could potentiate As-III in CML therapy.