Abstract
Paclitaxel, belongs to tubulin-binding agents (TBAs), shows a great efficacy against breast cancer via stabilizing microtubules. Drug resistance limits its clinical application. Here we aimed to explore a role of Polarity protein Par3 in improving paclitaxel effectiveness. Breast cancer specimens from 45 patients were collected to study the relationship between Par3 expression and paclitaxel efficacy. The Kaplan-Meier method was used for survival analysis. Cell viability was measured in breast cancer cells (SK-BR-3 and T-47D) with Par3 over-expression or knockdown. The flow cytometry assays were performed to measure cell apoptosis and cell cycle. BrdU incorporation assay and Hoechst 33,258 staining were performed to measure cell proliferation and cell apoptosis, respectively. Immunofluorescence was used to detect microtubule structures. Par3 expression was associated with good response of paclitaxel in breast cancer patients. Consistently, Par3 over-expression significantly sensitized breast cancer cells to paclitaxel by promoting cell apoptosis and reducing cell proliferation. In Par3 overexpressing cells upon paclitaxel treatment, we observed intensified cell cycle arrests at metaphase. Further exploration showed that Par3 over-expression stabilized microtubules of breast cancer cells in response to paclitaxel and resists to microtubules instability induced by nocodazole, a microtubule-depolymerizing agent. Par3 facilitates polymeric forms of tubulin and stabilizes microtubule structure, which aggravates paclitaxel-induced delay at the metaphase-anaphase transition, leading to proliferation inhibition and apoptosis of breast cancer cells. Par3 has a potential role in sensitizing breast cancer cells to paclitaxel, which may provide a more precise assessment of individual treatment and novel therapeutic targets.
Highlights
Breast cancer is the most commonly occurring malignant disease in women and the leading cause of cancer death among women.[1]
Further exploration showed that Par3 overexpression stabilizes microtubules of breast cancer cells in response to paclitaxel, and resists to microtubules instability induced by nocodazole, a microtubule-depolymerizing agent
Par3 has a potential role in sensitizing breast cancer cells to paclitaxel, which may provide a more precise assessment of individual treatment and novel therapeutic targets
Summary
Breast cancer is the most commonly occurring malignant disease in women and the leading cause of cancer death among women.[1]. Paclitaxel, one of the most commonly used taxanes, has shown great efficacy against breast cancer and is widely recognized as the first-line therapy.[2] paclitaxel resistance is one of the major causes of treatment failure, and became a great obstacle in clinical applications in breast cancer. Paclitaxel binds to β-tubulin in the α-β-tubulin heterodimer and stabilizes microtubules It functions as a mitotic inhibitor by restraining spindle microtubule dynamics and causing a delay at the metaphaseanaphase transition during mitosis. Extracellular signaling protein, such as TGFBI (transforming growth factor beta induced), may induce specific resistance to paclitaxel and mitotic spindle abnormalities in ovarian cancer cells, which was modulating by FAK- and Rho-dependent microtubules stabilization.[7]
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