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Published on: August 2, 2024
miR-145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6
Xiaolan Zhu1, Yuefeng Li, Chanjuan Xie
1The Fourth Affiliated Hospital of Jiangsu University, Department of gynecology, Zhenjiang, Jiangsu, China; Jiangsu University, school of medical science and laborratory medicine, Zhenjiang, Jiangsu, China.
Abstract:
Multidrug resistance (MDR) remains a major obstacle to effective chemotherapy treatment in ovarian cancer. In our study, paclitaxel-resistant ovarian cancer patients and cell lines had decreased miR-145 levels and expressed high levels of Sp1 and Cdk6. Introducing miR-145 into SKOV3/PTX and A2780/PTX cells led to a reduction in Cdk6 and Sp1 along with downregulation of P-gp and pRb. These changes resulted in increased accumulation of antineoplastic drugs and G1 cell cycle arrest, which rendered the cells more sensitive to paclitaxel in vitro and in vivo. These effects could be reversed by reintroducing Sp1 or Cdk6 into cells expressing high levels of miR-145, resulting in restoration of P-gp and pRb levels. Furthermore, we confirmed that both Cdk6 and Sp1 are targets of miR-145. Intriguingly, demethylation with 5-aza-dC led to reactivation of miR-145 expression in drug-resistant ovarian cancer cell lines, which also resulted in increased sensitivity to paclitaxel. Collectively, these findings begin to elucidate the role of miR-145 as an important regulator of chemoresistance in ovarian cancer by controlling both Cdk6 and Sp1.
Insights
MicroRNA-145 (miR-145) re-sensitizes ovarian cancer to chemotherapy by targeting Sp1 and Cdk6. Restoring miR-145 overcomes multidrug resistance (MDR), improving paclitaxel efficacy in ovarian cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Multidrug resistance (MDR) is a significant challenge in ovarian cancer chemotherapy.
- Decreased microRNA-145 (miR-145) and increased Sp1/Cdk6 levels are observed in paclitaxel-resistant ovarian cancer.
Purpose of the Study:
- To investigate the role of miR-145 in regulating chemoresistance in ovarian cancer.
- To explore the therapeutic potential of restoring miR-145 expression.
Main Methods:
- Assessed miR-145, Sp1, and Cdk6 levels in paclitaxel-resistant ovarian cancer cells and patients.
- Introduced miR-145 into resistant cells and evaluated changes in drug sensitivity, cell cycle, and protein expression.
- Confirmed Sp1 and Cdk6 as direct targets of miR-145.
- Investigated the effect of demethylation on miR-145 expression and drug sensitivity.
Main Results:
- Reduced miR-145 levels correlated with high Sp1 and Cdk6 expression in resistant cells.
- miR-145 restoration decreased Sp1/Cdk6, downregulated P-gp/pRb, induced G1 arrest, and enhanced paclitaxel sensitivity in vitro and in vivo.
- Reintroducing Sp1 or Cdk6 reversed these effects.
- Demethylation reactivated miR-145, increasing sensitivity to paclitaxel.
Conclusions:
- miR-145 acts as a crucial regulator of chemoresistance in ovarian cancer.
- Targeting Sp1 and Cdk6 by miR-145 offers a potential strategy to overcome MDR.
- miR-145 reactivation through demethylation may restore chemosensitivity.
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