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Chemical genomics with pyrvinium identifies C1orf115 as a regulator of drug efflux

Sanna N Masud1,2,3, Megha Chandrashekhar1,2,4, Michael Aregger2,5

  • 1Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

Nature Chemical Biology
|August 15, 2022
PubMed

Insights

Pyrvinium

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • Pyrvinium, a quinoline-derived cyanine dye, is an anti-helminthic drug with known anti-proliferative effects in cancer cells.
  • Pyrvinium's cytotoxic mechanisms, particularly its inhibition of WNT signaling and mitochondrial complex I, are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying pyrvinium's cytotoxicity.
  • To identify genetic factors mediating sensitivity and resistance to pyrvinium treatment.

Main Methods:

  • A pooled, genome-wide CRISPR loss-of-function screen was performed in HAP1 cells to identify genes affecting pyrvinium sensitivity.
  • Proximity-labeling experiments were used to investigate the physical association between C1orf115/RDD1 and ABCB1/MDR1.

Main Results:

  • The malate-aspartate and glycerol-3-phosphate shuttles were identified as mediators of pyrvinium-induced cytotoxicity via mitochondrial complex I inhibition.
  • Perturbation of C1orf115/RDD1 conferred resistance to pyrvinium by dysregulating the drug efflux pump ABCB1/MDR1.
  • C1orf115/RDD1 physically associates with ABCB1/MDR1 and regulates its localization and function.

Conclusions:

  • Pyrvinium's cytotoxicity involves mitochondrial complex I inhibition, modulated by metabolic shuttles.
  • C1orf115/RDD1 plays a critical role in pyrvinium resistance by regulating ABCB1/MDR1-mediated drug efflux.
  • These findings reveal a novel regulatory mechanism of drug resistance involving C1orf115/RDD1 and ABCB1/MDR1.

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