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Blockade of Rac1 activity induces G1 cell cycle arrest or apoptosis in breast cancer cells through downregulation of cyclin D1, survivin, and X-linked inhibitor of apoptosis protein.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2010 Jun; Vol. 9 (6), pp. 1657-68. Date of Electronic Publication: 2010 Jun 01. - Publication Year :
- 2010
-
Abstract
- Rac1 GTPase regulates a variety of signaling pathways that are implicated in malignant phenotypes. Here, we show that selective inhibition of Rac1 activity by the pharmacologic inhibitor NSC23766 suppressed cell growth in a panel of human breast cancer cell lines, whereas it had little toxicity to normal mammary epithelial cells. NSC23766 elicits its cytotoxicity via two distinct mechanisms in a cell line-dependent manner: induction of G(1) cell cycle arrest in cell lines (MDA-MB-231, MCF7, and T47D) that express retinoblastoma (Rb) protein or apoptosis in Rb-deficient MDA-MB-468 cells. In MDA-MB-231 cells, Rac1 inhibition induced G(1) cell cycle arrest through downregulation of cyclin D1 and subsequent dephosphorylation/inactivation of Rb. By contrast, MDA-MB-468 cells underwent substantial apoptosis that was associated with loss of antiapoptotic proteins survivin and X-linked inhibitor of apoptosis protein (XIAP). Rac1 knockdown by RNAi interference confirmed the specificity of NSC23766 and requirement for Rac1 in the regulation of cyclin D1, survivin, and XIAP in breast cancer cells. Further, NF-kappaB, but not c-Jun NH(2)-terminal kinase or p38 pathways, mediates the survival signal from Rac1. Overall, our results indicate that Rac1 plays a central role in breast cancer cell survival through regulation of NF-kappaB-dependent gene products.
- Subjects :
- Aminoquinolines pharmacology
Breast Neoplasms enzymology
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Down-Regulation drug effects
Epithelial Cells drug effects
Epithelial Cells enzymology
Epithelial Cells pathology
Extracellular Signal-Regulated MAP Kinases metabolism
Female
Humans
Inhibitor of Apoptosis Proteins
JNK Mitogen-Activated Protein Kinases metabolism
MAP Kinase Signaling System drug effects
Mammary Glands, Human pathology
NF-kappa B metabolism
Neoplasm Proteins metabolism
Pyrimidines pharmacology
Survivin
p38 Mitogen-Activated Protein Kinases metabolism
rac1 GTP-Binding Protein metabolism
Apoptosis drug effects
Breast Neoplasms pathology
Cyclin D1 metabolism
G1 Phase drug effects
Microtubule-Associated Proteins metabolism
X-Linked Inhibitor of Apoptosis Protein metabolism
rac1 GTP-Binding Protein antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 9
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 20515940
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-09-0906