Gefitinib and luteolin cause growth arrest of human prostate cancer PC-3 cells via inhibition of cyclin G-associated kinase and induction of miR-630.

Abstract

Cyclin G-associated kinase (GAK), a key player in clathrin-mediated membrane trafficking, is overexpressed in various cancer cells. Here, we report that GAK expression is positively correlated with the Gleason score in surgical specimens from prostate cancer patients. Embryonic fibroblasts from knockout mice expressing a kinase-dead (KD) form of GAK showed constitutive hyper-phosphorylation of the epidermal growth factor receptor (EGFR). In addition to the well-known EGFR inhibitors gefitinib and erlotinib, the dietary flavonoid luteolin was a potent inhibitor of the Ser/Thr kinase activity of GAK in vitro. Co-administration of luteolin and gefitinib to PC-3 cells had a greater effect on cell viability than administration of either compound alone; this decrease in viability was associated with drastic down-regulation of GAK protein expression. A comprehensive microRNA array analysis revealed increased expression of miR-630 and miR-5703 following treatment of PC-3 cells with luteolin and/or gefitinib, and exogenous overexpression of miR-630 caused growth arrest of these cells. GAK appears to be essential for cell death because co-administration of gefitinib and luteolin to EGFR-deficient U2OS osteosarcoma cells also had a greater effect on cell viability than administration of either compound alone. Taken together, these findings suggest that GAK may be a new therapeutic target for prostate cancer and osteosarcoma.

• Authors: Minami A Sakurai, Yuki Ozaki, Daisuke Okuzaki, Yoko Naito, Towa Sasakura, Ayumi Okamoto, Hiroe Tabara, Takao Inoue, Man Hagiyama, Akihiko Ito, Norikazu Yabuta, Hiroshi Nojima
• Journal: PloS one (PLoS One) Vol. 9 Issue 6 Pg. e100124 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24971999 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Intracellular Signaling Peptides and Proteins
• MIRN630 microRNA, human
• MicroRNAs
• Protein Kinase Inhibitors
• Quinazolines
• ErbB Receptors
• GAK protein, human
• Protein Serine-Threonine Kinases
• Luteolin
• Gefitinib

Topics

• Active Transport, Cell Nucleus
• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• ErbB Receptors (metabolism)
• Gefitinib
• Gene Expression
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, genetics, metabolism)
• Luteolin (administration & dosage, pharmacology)
• Male
• MicroRNAs (genetics)
• Models, Biological
• Neoplasm Grading
• Phosphorylation
• Prostatic Neoplasms (genetics, metabolism, pathology, surgery)
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Protein Transport
• Quinazolines (administration & dosage, pharmacology)
• Signal Transduction