The PMA phorbol ester tumor promoter increases canonical Wnt signaling via macropinocytosis
Nydia Tejeda-Munoz,
Yagmur Azbazdar,
Julia Monka,
Grace Binder,
Alex Dayrit,
Raul Ayala,
Neil O'Brien,
Edward M De Robertis
Affiliations
Nydia Tejeda-Munoz
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; Department of Oncology Science, Health Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, United States
Yagmur Azbazdar
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
Julia Monka
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
Grace Binder
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
Alex Dayrit
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
Raul Ayala
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
Neil O'Brien
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
Activation of the Wnt pathway lies at the core of many human cancers. Wnt and macropinocytosis are often active in the same processes, and understanding how Wnt signaling and membrane trafficking cooperate should improve our understanding of embryonic development and cancer. Here, we show that a macropinocytosis activator, the tumor promoter phorbol 12-myristate 13-acetate (PMA), enhances Wnt signaling. Experiments using the Xenopus embryo as an in vivo model showed marked cooperation between the PMA phorbol ester and Wnt signaling, which was blocked by inhibitors of macropinocytosis, Rac1 activity, and lysosome acidification. Human colorectal cancer tissue arrays and xenografts in mice showed a correlation of cancer progression with increased macropinocytosis/multivesicular body/lysosome markers and decreased GSK3 levels. The crosstalk between canonical Wnt, focal adhesions, lysosomes, and macropinocytosis suggests possible therapeutic targets for cancer progression in Wnt-driven cancers.
