Down-regulation of Raf-1 kinase is associated with paclitaxel resistance in human breast cancer MCF-7/Adr cells.

Abstract

Experiments were carried out to determine the role of Raf-1 kinase in the development of drug resistance and apoptosis induced by paclitaxel. In the present study, paclitaxel sensitivity, Raf-1 activity and mitogen-activated protein kinases activation were compared in two cell lines: parental human breast cancer cells and its drug resistant variant (MCF-7/Adr) cells. Paclitaxel treatment of parental MCF-7 cells caused a marked inhibition of Raf-1 kinase activity, concomitant with its mobility shift after 18 h exposure. In addition, paclitaxel greatly increased c-Jun N-terminal protein kinase (JNK) activity whereas showing a small enhancing effect on extracellular-regulated kinases (ERK) activity. Interestingly, MCF-7/Adr cells have lower basal Raf-1 activity, yet have much higher basal ERK activity than parental cells. However, it appeared that PD 98059, which turns off ERK through mitogen-activated protein kinase kinase (MEK) inhibition, enhanced basal Raf-1 kinase activity in MCF-7/Adr cells. Thus, the findings suggest that paclitaxel-induced apoptosis is mediated by JNK and occurs in parallel with suppression of the Raf-1 kinase activity in parental MCF-7 cells. In addition, down-regulation of Raf-1 kinase, which can be induced through the sustained ERK activation, may contribute to the development of acquired resistance in MCF-7/Adr cells.

• Authors: Michael Lee, Woo Suk Koh, Sang Seop Han
• Journal: Cancer letters (Cancer Lett) Vol. 193 Issue 1 Pg. 57-64 (Apr 10 2003) ISSN: 0304-3835 [Print] Ireland
• PMID: 12691824 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Flavonoids
• Proto-Oncogene Proteins c-raf
• Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinase Kinases
• Paclitaxel
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Apoptosis
• Breast Neoplasms (drug therapy, enzymology)
• Dose-Response Relationship, Drug
• Down-Regulation
• Drug Resistance, Neoplasm
• Enzyme Activation
• Enzyme Inhibitors (pharmacology)
• Flavonoids (pharmacology)
• Humans
• Immunoblotting
• MAP Kinase Signaling System
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• Paclitaxel (pharmacology)
• Phosphorylation
• Precipitin Tests
• Proto-Oncogene Proteins c-raf (biosynthesis)
• Time Factors
• Tumor Cells, Cultured