Suppression of phospho-p85α–GTP-Rac1 lipid raft interaction by bichalcone analog attenuates cancer cell invasion

Hui Li Lu, Shih Shun Chen, Wen Tung Hsu, Yao Cheng Lu, Chuan Chun Lee, Tian Shung Wu, Meng Liang Lin

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

The p85α subunit of phosphatidylinositol 3-kinase (PI3K) acts as a key regulator of cell proliferation and motility, which mediates signals that confer chemoresistance to many human cancer cells. Using small interfering RNAs against matrix metalloproteinase-2 (MMP-2) and the MMP-2 promoter-driven luciferase assay, we showed that the new synthetic bichalcone analog TSWU-CD4 inhibits the invasion of human cancer cells by down-regulating MMP-2 expression. Treatment with TSWU-CD4 inhibited MMP-2 expression and cell invasion, which were restored by ectopic wild type (wt) p85α or a constitutively active form of MAPK kinase 3 (CA MKK3), CA MKK6, or CA p38α mitogen-activated protein kinase (MAPK). The attenuated formation of lipid raft-associated phospho (p)-p85α–GTP-Rac1 complexes, protein kinase B (Akt) Ser 473 phosphorylation, and cell invasion by TSWU-CD4 was reversed by overexpression of wt p85α or the p85α Brc-homology (BH) domain. The ectopic expression of CA Rac1L61 (but not wt Rac1) could overcome the suppression of Ser 473 phosphorylation, lipid raft association of Akt, the interaction between GTP-bound Rac1 and p85α in lipid rafts, and cell invasion by TSWU-CD4. The involvement of Akt activity in the functions of NF-κB-mediated MMP-2 was further confirmed through the attenuation of Akt phosphorylation signaling using the Akt-specific inhibitor MK-2206 and ectopic expression of NF-κB p65. Collectively, the inhibitory effect of TSWU-CD4 on cancer cell invasion was likely to suppress the p-p85α–GTP-Rac1 interaction in lipid rafts by targeting the p85α BH domain, which resulted in the suppression of MMP-2 expression via the PI3K–Akt-mediated ERK–MKK3/MKK6–p38 MAPK-NF-κB signaling pathway.

Original languageEnglish
Pages (from-to)2106-2120
Number of pages15
JournalMolecular Carcinogenesis
Volume55
Issue number12
DOIs
Publication statusPublished - 2016 Dec 1

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

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