Addition of exogenous diacylglycerol enhances Wnt/β-catenin signaling through stimulation of macropinocytosis

Yagmur Azbazdar; Nydia Tejeda-Munoz; Julia C Monka; Alex Dayrit; Grace Binder; Gunes Ozhan; Edward M De Robertis

doi:10.1016/j.isci.2023.108075

Addition of exogenous diacylglycerol enhances Wnt/β-catenin signaling through stimulation of macropinocytosis

iScience. 2023 Sep 28;26(10):108075. doi: 10.1016/j.isci.2023.108075. eCollection 2023 Oct 20.

Authors

Yagmur Azbazdar¹, Nydia Tejeda-Munoz^{1

2}, Julia C Monka¹, Alex Dayrit¹, Grace Binder¹, Gunes Ozhan^{3

4}, Edward M De Robertis¹

Affiliations

¹ Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1662, USA.
² Department of Oncology Science, Health Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA.
³ Department of Molecular Biology and Genetics, Izmir Institute of Technology, Urla, Izmir 35430, Türkiye.
⁴ Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, Inciralti-Balcova, Izmir 35340, Türkiye.

Abstract

Activation of Wnt signaling triggers macropinocytosis and drives many tumors. We now report that the exogenous addition of the second messenger lipid sn-1,2 DAG to the culture medium rapidly induces macropinocytosis. This is accompanied by potentiation of the effects of added Wnt3a recombinant protein or the glycogen synthase kinase 3 (GSK3) inhibitor lithium chloride (LiCl, which mimics Wnt signaling) in luciferase transcriptional reporter assays. In a colorectal carcinoma cell line in which mutation of adenomatous polyposis coli (APC) causes constitutive Wnt signaling, DAG addition increased levels of nuclear β-catenin, and this increase was partially inhibited by an inhibitor of macropinocytosis. DAG also expanded multivesicular bodies marked by the tetraspan protein CD63. In an in vivo situation, microinjection of DAG induced Wnt-like twinned body axes when co-injected with small amounts of LiCl into Xenopus embryos. These results suggest that the DAG second messenger plays a role in Wnt-driven cancer progression.

Keywords: Biomolecules; Cancer; Pathophysiology.