PEITC by regulating Aurora Kinase A reverses chemoresistance in breast cancer cells

Souvick, Biswas ; Elizabeth, Mahapatra ; Madhumita, Roy ; Sutapa, Mukherjee

Abstract

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.

Keyword(s)

Aurora-A; Chemoresistance; Paclitaxel; Phenethyl isothiocyanate; Threonine

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