Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences , Seoul, Republic of Korea.
Department of Neuro-sciences and Neuro-therapeutics, John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John's Health Center , Santa Monica, CA, USA.
Cell Cycle. 2020 Jul;19(13):1590-1601. doi: 10.1080/15384101.2020.1754584. Epub 2020 May 19.
p97 has recently emerged as a therapeutic target for cancer due to its essential functions in protein homeostasis. CB-5083 is a first-in-class, potent and selective ATP-competitive p97 inhibitor that induces proteotoxic stress in cancer cells. Potential mechanisms regulating the sensitivity of cells to p97 inhibition remain poorly studied. Here, we demonstrate that Thrombospondin-1 (THBS1) is a CB-5083-upregulated gene that helps confer resistance of HCT116 cells to CB-5083. Our immunoblotting and immunofluorescence data showed that CB-5083 significantly increases the steady-state abundance of THBS1. Blockade of THBS1 induction sensitized cells to CB-5083-mediated growth inhibition. Suppression of THBS1 caused an increase of CB-5083-induced sub-G1 population and caspase 3/7 activity suggesting that its function is linked to the survival of cancer cells in response to p97 inhibition. Altogether our data provide new evidence that THBS1 is important for the susceptibility of cells to p97 inhibition.
p97 最近因其在蛋白质动态平衡中的重要功能而成为癌症的治疗靶点。CB-5083 是一种首创的、有效且选择性的 ATP 竞争性 p97 抑制剂，可在癌细胞中诱导蛋白毒性应激。调节细胞对 p97 抑制敏感性的潜在机制仍研究甚少。在这里，我们证明了血小板反应蛋白-1（THBS1）是 CB-5083 上调的基因，有助于赋予 HCT116 细胞对 CB-5083 的耐药性。我们的免疫印迹和免疫荧光数据表明，CB-5083 显著增加了 THBS1 的稳定状态丰度。THBS1 诱导的阻断使细胞对 CB-5083 介导的生长抑制更加敏感。THBS1 的抑制导致 CB-5083 诱导的亚 G1 群体和 caspase 3/7 活性增加，表明其功能与癌细胞对 p97 抑制的存活有关。总之，我们的数据提供了新的证据，表明 THBS1 对于细胞对 p97 抑制的敏感性很重要。
