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PMA suppresses breast cancer cell proliferation via PKCε‐mediated P‐Rex1 downregulation (1148.5)
Author(s) -
Wong ChuuYun,
Xie Yan,
Abel Peter,
Scofield Margaret,
Tu Yaping
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1148.5
Subject(s) - protein kinase c , rex1 , cell growth , cancer research , downregulation and upregulation , chemistry , signal transduction , microbiology and biotechnology , biology , embryonic stem cell , biochemistry , gene , induced pluripotent stem cell
Upregulated phosphatidylinositol‐3,4,5‐trisphosphate‐dependent Rac exchange factor 1 (P‐Rex1) promotes tumorigenesis and metastasis of various cancers, and thus could be a potential therapeutic target. The present study was to investigate the role and mechanism underlying phorbol‐12‐myristate‐13‐acetate (PMA), a protein kinase C (PKC) activator, down‐regulation of P‐Rex1 in breast cancer cells. Western blot analysis showed that PMA treatment caused a time‐ and concentration‐dependent decrease in P‐Rex1 protein levels in breast cancer MCF‐7 and BT‐474 cells with a maximum reduction of 87.2 ± 1.1 and 57.0 ± 8.6 %, respectively, at a concentration of 10 ng/ml. Interestingly, either silence of P‐Rex1 by siRNA or PMA treatment inhibits breast cancer cell proliferation by over 70%, which can be attenuated by restoring P‐Rex1 expression. MCF‐7 cells express PMA‐sensitive PKCα, δ, ε, and η. The PKC general inhibitor Gö6983, but not the PKCα‐selective inhibitor Gö6976, blocked the PMA down‐regulation of P‐Rex1 expression and breast cancer cell proliferation. Overexpression of a constitutively active PKCε mutant suppressed P‐Rex1 expression and breast cancer cell proliferation, which was also blocked by Gö6983 treatment. In contrast, overexpression of wild‐type PKCε, wild‐type or constitutively active PKCδ and PKCη had no effect. Together, our data suggest that PMA suppresses breast cancer cell proliferation via PKCε‐mediated P‐Rex1 down‐regulation. Since P‐Rex1 is highly overexpressed in human breast cancers with estrogen receptor (ER) expression, our study may provide a novel strategy for development of chemotherapeutic agents for patients with ER positive tumors that develop resistance to anti‐estrogen therapies. Grant Funding Source : Supported by the National Institutes of Health (CA125661 and 5P20GM103489) and Nebraska State LB595