Division of Applied Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, South Korea.
Division of Applied Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, South Korea.
Cancer Lett. 2018 Jun 28;424:127-135. doi: 10.1016/j.canlet.2018.03.033. Epub 2018 Mar 27.
The plasticity of solid tumors between the epithelial and mesenchymal states critically influences their malignant progression and metastasis. The epithelial-mesenchymal transition (EMT), which supports cancer cell invasion and metastasis, is promoted by pro-survival members (e.g., Bcl-2 and Bcl-X) of the Bcl-2 protein family, which are well-known key apoptosis regulators. We found that Bcl-w, another pro-survival member, promotes EMT by increasing respiratory complex-I activity and reactive oxygen species (ROS) levels. In contrast, pro-apoptotic Bax facilitates mesenchymal-epithelial transition by binding to complex-I, which inhibits complex-I-induced ROS production. Functional antagonism between pro-survival and pro-apoptotic proteins in regulating tumor plasticity was directly confirmed by co-expressing Bax with Bcl-w or Bcl-X. Therefore, the balance between the functionally opposing Bcl-2 proteins appears to be a critical determinant of cancer cell phenotypes. We further showed that sub-lethal doses of γ-radiation induced EMT by increasing Bcl-X and Bcl-w levels and complex-I activity. We propose that Bcl-2 proteins and complex-I are potential targets for preventing tumor progression and the malignant actions of radiotherapy.
实体肿瘤在上皮和间充质状态之间的可塑性严重影响其恶性进展和转移。上皮-间充质转化（EMT）支持癌细胞的侵袭和转移，它是由 Bcl-2 蛋白家族的促生存成员（例如 Bcl-2 和 Bcl-X）促进的，这些成员是众所周知的关键凋亡调节剂。我们发现另一个促生存成员 Bcl-w 通过增加呼吸复合物-I 活性和活性氧（ROS）水平来促进 EMT。相比之下，促凋亡 Bax 通过与复合物-I 结合来促进间充质-上皮转化，从而抑制复合物-I 诱导的 ROS 产生。通过共表达 Bax 与 Bcl-w 或 Bcl-X 直接证实了促生存和促凋亡蛋白在调节肿瘤可塑性方面的功能拮抗作用。因此，功能相反的 Bcl-2 蛋白之间的平衡似乎是癌细胞表型的关键决定因素。我们还表明，亚致死剂量的 γ 辐射通过增加 Bcl-X 和 Bcl-w 水平以及复合物-I 活性来诱导 EMT。我们提出 Bcl-2 蛋白和复合物-I 是预防肿瘤进展和放射治疗恶性作用的潜在靶点。
