Cdk4/6 Inhibition Induces Epithelial-Mesenchymal Transition and Enhances Invasiveness in Pancreatic Cancer Cells

dc.contributor.authorLiu, Fang
dc.contributor.authorKorc, Murray
dc.contributor.departmentMedicine, School of Medicine
dc.date.accessioned2025-06-26T12:41:53Z
dc.date.available2025-06-26T12:41:53Z
dc.date.issued2012
dc.description.abstractAberrant 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.
dc.eprint.versionAuthor's manuscript
dc.identifier.citationLiu F, Korc M. Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012;11(10):2138-2148. doi:10.1158/1535-7163.MCT-12-0562
dc.identifier.urihttps://hdl.handle.net/1805/48997
dc.language.isoen_US
dc.publisherAmerican Association for Cancer Research
dc.relation.isversionof10.1158/1535-7163.MCT-12-0562
dc.relation.journalMolecular Cancer Therapeutics
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectPancreatic cancer
dc.subjectCell proliferation
dc.subjectBenzodioxoles
dc.subjectNeoplasm metastasis
dc.subjectSignal transduction
dc.subjectPiperazines
dc.titleCdk4/6 Inhibition Induces Epithelial-Mesenchymal Transition and Enhances Invasiveness in Pancreatic Cancer Cells
dc.typeArticle
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