School of Health Sciences, Wuhan University, No. 115, Donghu Road, Wuhan, 430071, Hubei, China.
NanYang Medical College, Nanyang, 473061, Henan, China.
Mol Cell Biochem. 2018 May;442(1-2):177-186. doi: 10.1007/s11010-017-3202-y. Epub 2017 Oct 13.
As a natural agent for chemotherapy, deguelin remarkably suppresses proliferation in numerous solid cancers. Nevertheless, the molecular mechanisms of its suppression are still insufficient. In our research, it was revealed that deguelin induced cell death of lung cancer cells (LCCs) by triggering expression of PUMA. Deguelin triggered PUMA induction independently of p53 via suppression of PI3K/AKT pathway, therefore stimulating Foxo3a to bind with PUMA promoter and stimulate its transcription. Subsequent to activation, PUMA motivated Bax as well as the intrinsic mitochondrial cell death pathway. Removal of PUMA from LCC cells led to deguelin resistance, suggesting deguelin-induced cell death was modulated by PUMA. Furthermore, we demonstrated that deguelin enhanced the chemotherapeutic sensitivity of doxorubicin in vitro and in vivo, which were associated with potentiated PUMA induction. Taken together, these results establish a critical role of PUMA in mediating the anticancer effects of deguelin in lung cancer cells and provide the rationale for clinical evaluation.
作为一种天然的化疗药物，去格尔林显著抑制了许多实体癌的增殖。然而，其抑制作用的分子机制仍不够充分。在我们的研究中，发现去格尔林通过触发 PUMA 的表达诱导肺癌细胞（LCC）的细胞死亡。去格尔林通过抑制 PI3K/AKT 通路，独立于 p53 触发 PUMA 诱导，从而刺激 Foxo3a 与 PUMA 启动子结合并刺激其转录。PUMA 激活后，促进 Bax 以及内在的线粒体细胞死亡途径。从 LCC 细胞中去除 PUMA 导致去格尔林耐药，表明去格尔林诱导的细胞死亡受 PUMA 调节。此外，我们证明去格尔林在体外和体内增强了阿霉素的化疗敏感性，这与增强的 PUMA 诱导有关。总之，这些结果确立了 PUMA 在介导去格尔林在肺癌细胞中的抗癌作用中的关键作用，并为临床评估提供了依据。
