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.
Elife. 2023 Oct 30;12:RP89141. doi: 10.7554/eLife.89141.
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 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.
Wnt 通路的激活是许多人类癌症的核心。Wnt 和巨胞饮作用通常在相同的过程中活跃，了解 Wnt 信号和膜运输如何合作应该能提高我们对胚胎发育和癌症的理解。在这里，我们表明，巨胞饮作用的激活剂，肿瘤促进剂佛波醇 12-肉豆蔻酸 13-乙酸酯（PMA），增强了 Wnt 信号。使用胚胎作为体内模型的实验表明，PMA 佛波醇酯与 Wnt 信号之间存在明显的合作，而巨胞饮作用、Rac1 活性和溶酶体酸化的抑制剂可以阻断这种合作。人结直肠癌组织阵列和小鼠异种移植显示，癌症进展与巨胞饮作用/多泡体/溶酶体标志物增加和 GSK3 水平降低相关。经典 Wnt、粘着斑、溶酶体和巨胞饮作用之间的串扰表明，在 Wnt 驱动的癌症中，癌症进展可能有潜在的治疗靶点。
