RRC ID 52049
Author Tanaka S, Suzuki K, Sakaguchi M.
Title The prolyl oligopeptidase inhibitor SUAM-14746 attenuates the proliferation of human breast cancer cell lines in vitro.
Journal Breast Cancer
Abstract BACKGROUND:Prolyl oligopeptidase (POP, EC is a serine peptidase that hydrolyzes post-proline peptide bonds in peptides that are <30 amino acids in length. We previously reported that POP inhibition suppressed the growth of NB-1 human neuroblastomas cells and KATO III human gastric cancer cells. POP activity is commonly elevated in many cancers, which includes breast cancer. However, the effect of POP inhibition as a candidate breast cancer therapy is unknown.
METHODS:The effects of POP inhibition and knockdown on the proliferation of cultured human estrogen receptor-positive (ER+) MCF7 and T47D, and ER-negative (ER-) MDA-MB-231 breast cancer cell lines and the MCF12A non-tumorigenic epithelial cell line were tested by analyzing their influence on cell proliferation (WST-1 assay), cell viability (trypan blue exclusion assay), and cell cycle arrest (cell cycle analysis, cell cycle regulator proteins expression).
RESULTS:POP-specific inhibitors 3-({4-[2-(E)-styrylphenoxy]butanoyl}-L-4-hydroxyprolyl)-thiazolidine (SUAM-14746) and benzyloxycarbonyl-thiopropyl-thioprolinal and RNAi-mediated POP knockdown inhibited the proliferation of MCF7 cells without inducing cell death. SUAM-14746-induced growth inhibition was also observed in T47D and MDA-MB-231 cells, but not in MCF12A cells. This growth inhibition was associated with G1 phase arrest; reduced cyclin D1 and D3, cyclin-dependent kinase 4 (CDK4), E2F1, and retinoblastoma protein (pRb) expression; and increased cyclin-dependent kinase inhibitor 1B (p27kip1) expression. Moreover, the SUAM-14746-mediated cell cycle arrest of MCF7 cells was associated with increased pRb2/p130 protein expression and an increase in the number of cells in the quiescent G0 state, as defined by low RNA levels.
CONCLUSIONS:SUAM-14746 inhibited breast cancer cell growth in a cytostatic manner without inducing lethality, and POP-specific inhibitors may be an effective treatment against ER+ and ER- breast cancer.
Volume 24(5)
Pages 658-666
Published 2017-9-1
DOI 10.1007/s12282-017-0752-5
PII 10.1007/s12282-017-0752-5
PMID 28070831
MeSH Breast Neoplasms / drug therapy* Breast Neoplasms / pathology Cell Line, Tumor Cell Proliferation / drug effects* Cell Survival / drug effects Cyclin D1 / metabolism Cyclin D3 / metabolism Cyclin-Dependent Kinase 4 / antagonists & inhibitors Cyclin-Dependent Kinase 4 / metabolism Cyclin-Dependent Kinase Inhibitor p27 / pharmacology E2F1 Transcription Factor / metabolism Female G1 Phase Cell Cycle Checkpoints / drug effects* Gene Knockdown Techniques Humans Proline / analogs & derivatives* Proline / pharmacology Proline / therapeutic use Protease Inhibitors / therapeutic use RNA Interference RNA, Small Interfering / metabolism Receptors, Estrogen / metabolism Retinoblastoma Binding Proteins / metabolism Serine Endopeptidases / genetics Serine Endopeptidases / metabolism* Thiazolidines / pharmacology* Thiazolidines / therapeutic use Ubiquitin-Protein Ligases / metabolism
IF 2.044
Times Cited 4
Human and Animal Cells MCF7(RCB1904)