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KIF2C promotes paclitaxel resistance by depolymerizing polyglutamylated microtubules
Yuan-Shao Pao1, Kuan-Ju Liao2, Ya-Chia Shiau3
1Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu City 300044, Taiwan.
Abstract:
The long-term effectiveness of paclitaxel is limited by chemoresistance. In this study, we elucidate the molecular mechanism by which kinesin family member 2C (KIF2C), a well-known microtubule depolymerase, contributes to the development of chemoresistance in triple-negative breast cancer (TNBC). We observed elevated levels of KIF2C, tubulin tyrosination, and polyglutamylation in human and mouse breast cancer cells resistant to paclitaxel. Additionally, these chemoresistant cells possessed cross-resistance to diverse microtubule-targeting agents (MTAs). We demonstrated that KIF2C preferentially depolymerizes polyglutamylated tubulin, even in the presence of paclitaxel. To counter this, we developed 7S9, a chemical inhibitor of KIF2C, that prohibits the dissociation of KIF2C from microtubules. The combination of 7S9 and paclitaxel significantly reduced tumorigenesis in chemoresistant TNBC model in mice. Moreover, 7S9 diminished cancer cell chemoresistance to several clinically available MTAs. Our findings elucidate the molecular mechanism of KIF2C-mediated chemoresistance and highlight KIF2C as a promising target for combating cross-resistance in TNBC.
Insights
Kinesin family member 2C (KIF2C) drives chemoresistance in triple-negative breast cancer (TNBC) by depolymerizing microtubules. Inhibiting KIF2C with 7S9 resensitizes resistant TNBC cells to paclitaxel and other microtubule-targeting agents.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Paclitaxel effectiveness is limited by chemoresistance in triple-negative breast cancer (TNBC).
- Kinesin family member 2C (KIF2C) is a microtubule depolymerase implicated in cancer progression.
Purpose of the Study:
- To elucidate the molecular mechanism of KIF2C in paclitaxel chemoresistance in TNBC.
- To evaluate KIF2C as a therapeutic target for overcoming chemoresistance.
Main Methods:
- Assessed KIF2C, tubulin tyrosination, and polyglutamylation levels in paclitaxel-resistant TNBC cells.
- Developed and tested 7S9, a KIF2C inhibitor, in combination with paclitaxel in mouse models.
- Investigated KIF2C's interaction with polyglutamylated tubulin.
Main Results:
- Elevated KIF2C, tubulin tyrosination, and polyglutamylation were observed in chemoresistant TNBC cells.
- KIF2C preferentially depolymerizes polyglutamylated tubulin, conferring cross-resistance to various microtubule-targeting agents (MTAs).
- Combination therapy with 7S9 and paclitaxel significantly reduced tumor growth in chemoresistant TNBC mouse models and diminished chemoresistance to clinically available MTAs.
Conclusions:
- KIF2C mediates chemoresistance in TNBC by targeting polyglutamylated tubulin.
- KIF2C inhibition represents a promising strategy to combat paclitaxel resistance and cross-resistance in TNBC.
- 7S9 demonstrates potential as an adjunct therapy for chemoresistant TNBC.
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