Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells.

Abstract

Aberrant activation of Cyclin D-Cdk4/6 signaling pathway is commonly found in pancreatic ductal adenocarcinoma (PDAC). Here, we show that PD-0332991, a highly specific inhibitor for Cdk4 and Cdk6, exerted growth inhibitory effects on three human PDAC cell lines. Microarray analysis revealed that PD-0332991 downregulated cell-cycle-related genes, but upregulated genes implicated in extracellular matrix (ECM) remodeling and pancreatic cancer cell invasion and metastasis. Moreover, PD-0332991 enhanced invasion in TGF-β-responsive PDAC cell lines that harbor a wild-type SMAD4 gene (COLO-357, PANC-1), but not in TGF-β-resistant AsPC-1 cells that harbor a mutated SMAD4. PD-0332991 also induced epithelial-mesenchymal transition (EMT) in COLO-357 and PANC-1, but not in AsPC-1 cells. Inhibition of CDK4/6 using shRNA mimicked the effects of PD-0332991 on EMT induction. Furthermore, PD-0332991 increased Smad transcriptional activity in luciferase readout assays and activated TGF-β signaling. SB-505124, an inhibitor of the type-I TGF-β receptor (TβRI) kinase, completely blocked EMT induction by PD-0332991. When combined with PD-0332991, SB-505124 inhibited the growth of COLO-357 and PANC-1 cells. Taken together, these data suggest that anti-Cdk4/6 therapy could induce EMT and enhance pancreatic cancer cell invasion by activating Smad-dependent TGF-β signaling, and that combining PD-0332991 and SB-505124 may represent a novel therapeutic strategy in PDAC.

• Authors: Fang Liu, Murray Korc
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 10 Pg. 2138-48 (Oct 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22869556 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 2-(5-benzo(1,3)dioxol-5-yl-2-tert-butyl-3H-imidazol-4-yl)-6-methylpyridine hydrochloride
• Benzodioxoles
• Imidazoles
• Piperazines
• Pyridines
• RNA, Small Interfering
• Smad Proteins
• Transforming Growth Factor beta
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6
• palbociclib

Topics

• Benzodioxoles (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors, metabolism)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors, metabolism)
• Drug Screening Assays, Antitumor
• Drug Synergism
• Epithelial-Mesenchymal Transition (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Humans
• Imidazoles (pharmacology)
• Neoplasm Invasiveness
• Neoplasm Metastasis (genetics)
• Pancreatic Neoplasms (enzymology, genetics, pathology)
• Piperazines
• Pyridines (pharmacology)
• RNA, Small Interfering (metabolism)
• Signal Transduction (drug effects, genetics)
• Smad Proteins (genetics, metabolism)
• Transcription, Genetic (drug effects)
• Transforming Growth Factor beta (pharmacology)
• Tumor Stem Cell Assay