{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T16:55:42Z","timestamp":1762102542006,"version":"build-2065373602"},"reference-count":61,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2020,8,13]],"date-time":"2020-08-13T00:00:00Z","timestamp":1597276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pharmacologic intervention to affect the membrane lipid homeostasis of lipid rafts is a potent therapeutic strategy for cancer. Here we showed that gallic acid (GA) caused the complex formation of inactive Ras-related C3 botulinum toxin substrate 1 (Rac1)-phospho (p)-casein kinase 2 \u03b1 (CK2\u03b1) (Tyr 255) in human tongue squamous carcinoma (TSC) cells, which disturbed the lipid raft membrane-targeting of phosphatidylinositol 3-kinase (PI3K)-Rac1-protein kinase B (Akt) signal molecules by inducing the association of p110\u03b1-free p85\u03b1 with unphosphorylated phosphatase tensin homolog deleted on chromosome 10 (PTEN) in lipid rafts. The effects on induction of inactive Rac1-p-CK2\u03b1 (Tyr 255) complex formation and attenuation of p-Akt (Ser 473), GTP-Rac1, glucose transporter-1 (GLUT-1) lipid raft membrane-targeting, and cell invasive activity by GA were counteracted either by CK2\u03b1 short hairpin RNA or cellular-Src (c-Src) inhibitor PP1. PP1 treatment, GLUT-1 or constitutively active Rac1 ectopic-expression blocked GA-induced decreases in cellular glucose, sphingolipid and cholesterol of lipid raft membranes, p85\u03b1-p110\u03b1-GTP-Rac1 complexes, glucosylceramide synthase activity and increase in ceramide and p110\u03b1-free p85\u03b1-PTEN complex levels of lipid raft membranes, which reversed the inhibition on matrix metalloproteinase (MMP)-2\/-9-mediated cell invasion induced by GA. Using transient ectopic expression of nuclear factor-kappa B (NF-\u03baB) p65, MMP-2\/-9 promoter-driven luciferase, and NF-\u03baB-dependent luciferase reporter genes and NF-\u03baB specific inhibitors or Rac1 specific inhibitor NSC23766, we confirmed that an attenuation of Rac1 activity by GA confers inhibition of NF-\u03baB-mediated MMP-2\/-9 expression and cell invasion. In conclusion, GA-induced c-Src activation is a key inductive event for the formation of inactive Rac1-p-CK2\u03b1 (Tyr 255) complexes, which disturbed lipid raft compartment of PI3K and PTEN molecules by impairing Akt-regulated GLUT-1-mediated sphingolipid synthesis, and finally resulting in inhibition of TSC cell invasion.<\/jats:p>","DOI":"10.3390\/ijms21165812","type":"journal-article","created":{"date-parts":[[2020,8,13]],"date-time":"2020-08-13T09:23:44Z","timestamp":1597310624000},"page":"5812","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Enforced C-Src Activation Causes Compartmental Dysregulation of PI3K and PTEN Molecules in Lipid Rafts of Tongue Squamous Carcinoma Cells by Attenuating Rac1-Akt-GLUT-1-Mediated Sphingolipid Synthesis"],"prefix":"10.3390","volume":"21","author":[{"given":"Chien-Wei","family":"Wu","sequence":"first","affiliation":[{"name":"Division of Laboratory, Armed Force Taichung General Hospital, Taichung 411228, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shyang-Guang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung 406053, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching-Hsiao","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medical Technology, Jen-The Junior College of Medicine, Nursing and Management, Miaoli 356006, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Ling","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Medical Enginerring, Asia University, Taichung 41354, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng-Liang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404394, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9152-929X","authenticated-orcid":false,"given":"Shih-Shun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung 406053, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e189","DOI":"10.1038\/oncsis.2015.49","article-title":"Lipid metabolic reprogramming in cancer cells","volume":"5","author":"Vasseur","year":"2016","journal-title":"Oncogenesis"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.molcel.2010.10.005","article-title":"Membranes in Balance: Mechanisms of Sphingolipid Homeostasis","volume":"40","author":"Breslow","year":"2010","journal-title":"Mol. 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