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Genetic screening reveals a link between Wnt signaling and antitubulin drugs

A H Khan1, J S Bloom2, E Faridmoayer1

  • 1Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.

The Pharmacogenomics Journal
|July 8, 2015
PubMed

Insights

Antitubulin drugs like paclitaxel and colchicine impact cell growth by affecting microtubules. Researchers found the ZNRF3 gene influences cell survival, revealing a link between microtubule dynamics and Wnt signaling.

Area of Science:

  • Cell Biology
  • Genetics
  • Pharmacology

Background:

  • Antitubulin drugs paclitaxel (PX) and colchicine (COL) are vital for inhibiting cell growth.
  • Clinically effective drug concentrations are significantly lower than those altering tubulin polymerization in vitro.
  • Identifying genetic targets is crucial for understanding drug mechanisms at therapeutic levels.

Purpose of the Study:

  • To map genetic targets influencing cell survival in the presence of medically relevant compounds.
  • To elucidate the role of specific genes in mediating cellular responses to antitubulin drugs at therapeutic concentrations.

Main Methods:

  • Utilized a human radiation hybrid panel for single-gene resolution genetic mapping.
  • Assessed cell survival in the presence of paclitaxel, colchicine, and other compounds.
  • Employed overexpression and small interfering RNA (siRNA) knockdown of the ZNRF3 gene.
  • Investigated the effect of a Wnt signaling inhibitor (Wnt-C59).

Main Results:

  • The zinc and ring finger 3 (ZNRF3) gene emerged as a dominant genetic factor affecting cell survival with PX and COL at therapeutic concentrations.
  • ZNRF3, an inhibitor of Wingless/Int (Wnt) signaling, shielded cells when overexpressed and sensitized them upon knockdown.
  • Pharmacological inhibition of Wnt signaling with Wnt-C59 protected cells from PX and COL toxicity.

Conclusions:

  • Antitubulin drugs perturb microtubule dynamics, which in turn influences Wnt signaling pathways.
  • ZNRF3 plays a critical role in mediating cellular sensitivity to antitubulin drugs at clinically relevant concentrations.
  • This study reveals a novel connection between microtubule function and Wnt signaling regulation.

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