Palbociclib inhibits epithelial-mesenchymal transition and metastasis in breast cancer via c-Jun/COX-2 signaling pathway.

Abstract

Palbociclib, a highly selective CDK4/6 inhibitor, has been shown to be a novel anti-tumor agent that suppresses breast cancer cell proliferation. However, its anti-metastasis activity remains controversial. In the present study, we evaluated whether palbociclib prevented breast cancer cell metastasis and revealed its regulatory mechanism. We found that palbociclib inhibited migration and invasion in the breast cancer cells MDA-MB-231 and T47D. The epithelial-mesenchymal transition (EMT) markers, vimentin and Snail, were down-regulated with palbociclib treatment. Moreover, we revealed that this inhibition was mediated by the c-Jun/COX-2 pathway. COX-2 was decreased after palbociclib treatment. The production of PGE2 was also reduced along with COX-2. Additionally, our data showed that c-Jun, a crucial transcriptional regulator of COX-2, was down-regulated by palbociclib. We found that palbociclib weakened the COX-2 promoter binding activity of c-Jun and prevented its translocation from the cytoplasm to cell nuclei. Bioluminescence imaging and tail intravenous injection were used to evaluate the anti-metastasis effect of palbociclib in vivo. The data demonstrated that palbociclib reduced breast cancer metastasis to the lung. These results therefore demonstrated that the anti-metastasis activity of palbociclib is mediated via the c-Jun/COX-2 signaling pathway by inhibiting EMT in breast cancer cells.

• Authors: Ge Qin, Fei Xu, Tao Qin, Qiufan Zheng, Dingbo Shi, Wen Xia, Yun Tian, Yanlai Tang, Jingshu Wang, Xiangshen Xiao, Wuguo Deng, Shusen Wang
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 39 Pg. 41794-808 (Dec 08 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26540629 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cyclooxygenase 2 Inhibitors
• Piperazines
• Proto-Oncogene Proteins c-jun
• Pyridines
• Retinoblastoma Protein
• Cyclooxygenase 2
• PTGS2 protein, human
• palbociclib
• Dinoprostone

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Binding Sites
• Breast Neoplasms (drug therapy, enzymology, genetics, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cyclooxygenase 2 (genetics, metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Dinoprostone (metabolism)
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (enzymology, genetics, prevention & control, secondary)
• Mice, Nude
• Phosphorylation
• Piperazines (pharmacology)
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-jun (genetics, metabolism)
• Pyridines (pharmacology)
• Retinoblastoma Protein (metabolism)
• Signal Transduction (drug effects)
• Transfection
• Xenograft Model Antitumor Assays