Stathmin dynamics modulate the activity of eribulin in breast cancer cells
Mikihiro Yoshie1, Akari Ishida1, Haruka Ohashi1
1Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan.
Abstract:
Stathmin, a phosphoprotein that modulates microtubule dynamics, is highly expressed in breast cancer cells. Eribulin, a microtubule-depolymerizing agent, is used to treat patients with advanced breast cancer. However, the detailed mechanisms underlying the action of eribulin during microtubule catastrophe, and the interaction between eribulin and stathmin dynamics, remain unclear. Here, we investigated the role of stathmin in the antiproliferative activity of eribulin in breast cancer cells. Eribulin induced phosphorylation of stathmin in MCF7 and MDA-MB-231 cells; this was attenuated by an inhibitor of protein kinase A (H89) and an inhibitor of Ca2+ /calmodulin-dependent kinase II (KN62). In addition, expression of phosphorylated stathmin was reduced by the protein phosphatase PP2A activator FTY720 but increased by the PP2A inhibitor okadaic acid. Of note, expression of PP2A subunits in eribulin-treated cells decreased, although eribulin did not affect the phosphatase activity of recombinant PP2A directly. Furthermore, the antiproliferative effect of eribulin was stronger in stathmin-overexpressing cells. These results suggest that stathmin dynamics are closely associated with the antiproliferative effects of eribulin and stathmin is a possible biomarker for predicting the therapeutic effects of eribulin in breast cancer patients.
Insights
Stathmin phosphorylation influences eribulin
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Stathmin, a microtubule-regulating phosphoprotein, is highly expressed in breast cancer.
- Eribulin is a microtubule-depolymerizing agent used for advanced breast cancer treatment.
- The precise mechanisms of eribulin's action and its interaction with stathmin are not fully understood.
Purpose of the Study:
- To investigate stathmin's role in eribulin's antiproliferative activity in breast cancer cells.
- To elucidate the signaling pathways regulating stathmin phosphorylation in response to eribulin.
Main Methods:
- Investigated eribulin's effect on stathmin phosphorylation in MCF7 and MDA-MB-231 cells.
- Utilized protein kinase A (H89) and Ca2+/calmodulin-dependent kinase II (KN62) inhibitors.
- Examined the impact of protein phosphatase 2A (PP2A) activators (FTY720) and inhibitors (okadaic acid) on stathmin phosphorylation.
- Assessed the effect of eribulin on PP2A subunit expression and activity.
- Compared eribulin's antiproliferative effects in stathmin-overexpressing versus control cells.
Main Results:
- Eribulin induced stathmin phosphorylation, which was modulated by protein kinase A and Ca2+/calmodulin-dependent kinase II.
- Phosphorylated stathmin levels were decreased by PP2A activation and increased by PP2A inhibition.
- Eribulin treatment led to decreased expression of PP2A subunits.
- The antiproliferative effect of eribulin was enhanced in cells overexpressing stathmin.
Conclusions:
- Stathmin phosphorylation dynamics are closely linked to eribulin's antiproliferative effects in breast cancer.
- Stathmin may serve as a predictive biomarker for eribulin's therapeutic efficacy in breast cancer patients.
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