2. Academic Validation
  3. Chemical genomics with pyrvinium identifies C1orf115 as a regulator of drug efflux

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

  • Nat Chem Biol. 2022 Dec;18(12):1370-1379. doi: 10.1038/s41589-022-01109-0.
Sanna N Masud # 1 2 3,  Megha Chandrashekhar # 1 2 4,  Michael Aregger 2 5,  Guihong Tan 2,  Xiaoyu Zhang 2,  Patricia Mero 2 3,  David A Pirman 3,  Olga Zaslaver 2,  Gromoslaw A Smolen 6 7,  Zhen-Yuan Lin 8,  Cassandra J Wong 8,  Charles Boone 1 2,  Anne-Claude Gingras 1 8,  J Rafael Montenegro-Burke 1 2,  Jason Moffat 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 2 Donnelly Centre, Toronto, ON, Canada.
  • 3 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
  • 4 Canadian Nuclear Laboratories, Chalk River, ON, Canada.
  • 5 Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
  • 6 Agios Pharmaceuticals, Cambridge, MA, USA.
  • 7 Celsius Therapeutics, Cambridge, MA, USA.
  • 8 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
  • 9 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. [email protected].
  • 10 Donnelly Centre, Toronto, ON, Canada. [email protected].
  • 11 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
  • 12 Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada. [email protected].
  • # Contributed equally.
PMID: 35970996 DOI: 10.1038/s41589-022-01109-0
Abstract

Pyrvinium is a quinoline-derived cyanine dye and an approved anti-helminthic drug reported to inhibit Wnt signaling and have anti-proliferative effects in various Cancer cell lines. To further understand the mechanism by which pyrvinium is cytotoxic, we conducted a pooled genome-wide CRISPR loss-of-function screen in the human HAP1 cell model. The top drug-gene sensitizer interactions implicated the malate-aspartate and glycerol-3-phosphate shuttles as mediators of cytotoxicity to mitochondrial complex I inhibition including pyrvinium. By contrast, perturbation of the poorly characterized gene C1orf115/RDD1 resulted in strong resistance to the cytotoxic effects of pyrvinium through dysregulation of the major drug efflux pump ABCB1/MDR1. Interestingly, C1orf115/RDD1 was found to physically associate with ABCB1/MDR1 through proximity-labeling experiments and perturbation of C1orf115 led to mis-localization of ABCB1/MDR1. Our results are consistent with a model whereby C1orf115 modulates drug efflux through regulation of the major drug exporter ABCB1/MDR1.

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