Department of Pharmacology, Chinese Academy of Medical Sciences, Beijing 100050, People's Republic of China.
Mol Med Rep. 2011 Jul-Aug;4(4):739-46. doi: 10.3892/mmr.2011.494. Epub 2011 May 16.
Breast cancer is one of the most common malignant diseases among women. In early and metastatic breast cancer, Taxane (Taxol) is widely used as an adjuvant and neoadjuvant therapies. Although breast cancer is initially responsive to Taxol, inherent or developed resistance to Taxol often limits the efficacy of the drug. The oncogene Aurora kinase A is frequently up-regulated in human cancer, and is associated with sensitivity to chemotherapy in certain types of cancer. In the present study, we aimed to clarify the functional role of Aurora kinase A in breast cancer resistance to Taxol, and to determine the means to overcome this resistance. The correlation between the expression levels of Aurora kinase A and chemoresistance to Taxol in breast cancer cells, and resistance to Taxol in a xenograft model were demonstrated. MTT assay was performed to determine cell viability. Subsequently, the relationship of Aurora kinase A with the expression and functional role of P-gp was clarified, as well as its relationship with p-ERK2, which regulates the expression of P-gp. The expression of Aurora A was determined to be capable of enhancing the sensitivity of cells resistant to Taxol in vitro and in vivo using stable knockdown Aurora kinase A cells. We propose that this kinase may be used as a target for overcoming chemoresistance and enhancing the chemosensitivity of breast cancer to Taxol.
乳腺癌是女性中最常见的恶性疾病之一。在早期和转移性乳腺癌中，紫杉烷（紫杉醇）被广泛用作辅助和新辅助治疗药物。尽管乳腺癌最初对紫杉醇敏感，但紫杉醇的固有或获得性耐药常常限制了药物的疗效。癌基因 Aurora 激酶 A 在人类癌症中经常上调，并且与某些类型癌症的化疗敏感性相关。在本研究中，我们旨在阐明 Aurora 激酶 A 在乳腺癌对紫杉醇耐药中的功能作用，并确定克服这种耐药性的方法。证明了 Aurora 激酶 A 的表达水平与乳腺癌细胞对紫杉醇的化疗耐药性以及异种移植模型中对紫杉醇的耐药性之间的相关性。通过 MTT 测定法确定细胞活力。随后，阐明了 Aurora 激酶 A 与 P-gp 的表达和功能作用之间的关系，以及与调节 P-gp 表达的 p-ERK2 之间的关系。使用稳定敲低 Aurora 激酶 A 细胞，确定 Aurora A 的表达能够增强体外和体内对紫杉醇耐药细胞的敏感性。我们提出，这种激酶可作为克服化疗耐药性和增强乳腺癌对紫杉醇化疗敏感性的靶标。
