Zhou Xiao, Huang Zhen, Yang Huawei, Jiang Yi, Wei Wei, Li Qiuyun, Mo Qinguo, Liu Jianlun
Department of Breast Surgery, the Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Department of Breast Surgery, the Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Biomed Pharmacother. 2017 Jul;91:504-509. doi: 10.1016/j.biopha.2017.04.113. Epub 2017 May 4.
The resistance to therapy is a major clinical challenge for advanced stage breast cancer. Identification of novel potential therapeutic targets is needed to overcome chemoresistance. In this work, we identified a target that was critically involved in breast cancer growth and chemoresistance. We demonstrated that β-glucosidase expression and activity were significantly upregulated in breast cancer tissues and a panel of cell lines compared to normal adjacent breast tissues and cell lines. β-glucosidase overexpression activated PI3K/Akt/mTOR signalling, leading to increased cell growth. In contrast, β-glucosidase inhibition by siRNA depletion and pharmacological approach using conduritol B epoxide (selective β-glucosidase inhibitor) suppressed growth and induced apoptosis in breast cancer cells. Importantly, β-glucosidase inhibition significantly sensitized breast cancer cells to chemotherapy in vitro and in vivo, suggesting that inhibiting β-glucosidase effectively targeted breast cancer cells that were resistant to elimination by chemotherapeutic agent alone. We demonstrated the positive role of β-glucosidase in breast cancer growth and survival. Our work also suggested that inhibiting β-glucosidase as a possible alternative therapeutic strategy to overcome chemoresistance in breast cancer.
对治疗的抗性是晚期乳腺癌面临的一项重大临床挑战。需要鉴定新的潜在治疗靶点以克服化疗抗性。在这项研究中，我们鉴定出了一个在乳腺癌生长和化疗抗性中起关键作用的靶点。我们证明，与相邻正常乳腺组织和细胞系相比，β-葡萄糖苷酶的表达和活性在乳腺癌组织及一组细胞系中显著上调。β-葡萄糖苷酶的过表达激活了PI3K/Akt/mTOR信号传导，导致细胞生长增加。相反，通过小干扰RNA（siRNA）耗竭和使用conduritol B环氧化物（选择性β-葡萄糖苷酶抑制剂）的药理学方法抑制β-葡萄糖苷酶，可抑制乳腺癌细胞的生长并诱导其凋亡。重要的是，抑制β-葡萄糖苷酶在体外和体内均能使乳腺癌细胞对化疗显著敏感，这表明抑制β-葡萄糖苷酶可有效靶向单独使用化疗药物难以清除的乳腺癌细胞。我们证明了β-葡萄糖苷酶在乳腺癌生长和存活中的积极作用。我们的研究还表明，抑制β-葡萄糖苷酶可能是克服乳腺癌化疗抗性的一种替代治疗策略。
