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PEITC by regulating Aurora Kinase A reverses chemoresistance in breast cancer cells
Indian Journal of Biochemistry and Biophysics ( IF 1.5 ) Pub Date : 2020-04-27
Souvick Biswas, Elizabeth Mahapatra, Madhumita Roy, Sutapa Mukherjee

Development of acquired chemoresistance renders a challenge in breast cancer therapy. Aurora kinases, a family of serine/threonine mitotic kinases play pivotal roles in the acquirement of chemoresistance. Aurora A is intricately associated with mitotic events and is overexpressed in different cancers including breast cancer. Amplification or overexpression Aurora A confers chemoresistance and are considered as a promising therapeutic target in cancers. Therefore, targeting Aurora A by natural means particularly by using Phenethyl isothiocyanate (PEITC), a natural isothiocyanate might be an effective strategy for reversing resistance towards chemotherapeutics. The present study investigated the modulatory role of PEITC on Aurora A and their downstream target proteins in breast adenocarcinoma cell line (MCF-7) and its paclitaxel-resistant counterpart; designated as MCF-7Pacli/R. Paclitaxel resistance was warranted by P-gp1, MRP1, Ki-67 overexpression, rhodamine 123 accumulations and upregulation of Aurora-A along with phospho-IκBα. Multidrug resistance was confirmed by MTT assay. Western blotting, RT-PCR analysis revealed overexpression of Aurora-A in MCF-7Pacli/R cells; which was eventually diminished by PEITC. PEITC by targeting Aurora A and their downstream proteins (phospho-p53, phospho-IκBα) acted as a resistance-modifying agent and ultimately led to paclitaxel- induced apoptosis. These findings demonstrated that PEITC reverses chemoresistance by regulating Aurora A and restores chemosensitivity towards paclitaxel.

中文翻译:

PEITC通过调节Aurora激酶A逆转乳腺癌细胞的化学耐药性

获得性化学抗性的发展在乳腺癌治疗中提出了挑战。Aurora激酶是丝氨酸/苏氨酸有丝分裂激酶家族,在获得化学抗性中起关键作用。极光A与有丝分裂事件密切相关,并且在包括乳腺癌在内的不同癌症中过表达。扩增或过表达Aurora A赋予化学抗性,被认为是癌症中有希望的治疗靶标。因此,通过天然手段特别是通过使用异硫氰酸苯乙酯(PEITC)靶向Aurora A,天然异硫氰酸酯可能是逆转对化学疗法耐药性的有效策略。本研究调查了PEITC对乳腺腺癌细胞系(MCF-7)及其耐紫杉醇的Aurora A及其下游靶蛋白的调节作用。指定为MCF-7Pacli / R。P-gp1,MRP1,Ki-67过表达,若丹明123积累以及Aurora-A和磷酸化IκBα的上调可确保紫杉醇具有抗药性。通过MTT分析证实了多药耐药性。蛋白质印迹,RT-PCR分析显示Aurora-A在MCF-7Pacli / R细胞中过度表达。最终被PEITC减少了。PEITC通过靶向Aurora A及其下游蛋白(磷酸化p53,磷酸化IκBα)充当抗性修饰剂,并最终导致紫杉醇诱导的细胞凋亡。
更新日期:2020-04-27
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