Hwang Inwoo, Kim Chung Kwon, Ko Hyo Rim, Park Kye Won, Cho Sung-Woo, Ahn Jee-Yin
Department of Molecular Cell Biology, Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon 16419, Korea.
Sci Rep. 2016 Jul 28;6:30626. doi: 10.1038/srep30626.
Potential tumor suppressor p42, ErbB3-binding protein 1 (EBP1) inhibits phosphoinositide 3-kinase (PI3K) activity reducing the p85 regulatory subunit. In this study, we demonstrated that overexpression of p42 promoted not only a reduction of wild type of p85 subunit but also oncogenic mutant forms of p85 which were identified in human cancers. Moreover, we identified the small fragment of C-terminal domain of p42 is sufficient to exhibit tumor suppressing activity of p42-WT, revealing that this small fragment (280-394) of p42 is required for the binding of both HSP70 and CHIP for a degradation of p85. Furthermore, we showed the small fragment of p42 markedly inhibited the tumor growth in mouse xenograft models of brain and breast cancer, resembling tumor suppressing activity of p42. Through identification of the smallest fragment of p42 that is responsible for its tumor suppressor activity, our findings represent a novel approach for targeted therapy of cancers that overexpress PI3K.
潜在的肿瘤抑制因子p42，即ErbB3结合蛋白1（EBP1），可抑制磷酸肌醇3激酶（PI3K）活性，减少p85调节亚基。在本研究中，我们证明p42的过表达不仅促进野生型p85亚基减少，还促进在人类癌症中鉴定出的致癌突变形式的p85减少。此外，我们鉴定出p42 C末端结构域的小片段足以展现p42野生型的肿瘤抑制活性，这表明p42的这个小片段（280-394）是HSP70和CHIP结合以降解p85所必需的。此外，我们发现p42的小片段在脑癌和乳腺癌的小鼠异种移植模型中显著抑制肿瘤生长，类似于p42的肿瘤抑制活性。通过鉴定p42负责其肿瘤抑制活性的最小片段，我们的发现代表了一种针对过表达PI3K的癌症进行靶向治疗的新方法。
