Lu Xinyan, Chen Dongshi, Wang Min, Song Xiangping, Ermine Kaylee, Hao Suisui, Jha Anupma, Huang Yixian, Kang Ying, Qiu Haibo, Lenz Heinz-Josef, Li Song, Jin Zhendong, Yu Jian, Zhang Lin
Department of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, CA, USA.
Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA, USA.
Cell Death Differ. 2025 May 6. doi: 10.1038/s41418-025-01521-8.
Oxysterol-binding proteins (OSBPs), lipid transfer proteins functioning at intracellular membrane contact sites, are recently found to be dysregulated in cancer and promote cancer cell survival. However, their role as potential targets in cancer therapy remains largely unexplored. In this study, we found OSW-1, a natural compound and OSBP inhibitor, potently and selectively kills colon cancer cells by activating a previously unknown necroptosis pathway that is independent of receptor-interacting protein 1 (RIP1) and RIP3. OSW-1 stabilizes p53 and degrades OSBPs to promote endoplasmic reticulum (ER) stress and glycogen synthase kinase 3β (GSK3β)/Tip60-mediated p53 acetylation at Lysine 120, which selectively induces its target PUMA. PUMA-mediated mitochondrial calcium influx activates calcium/calmodulin-dependent protein kinase IIδ (CamKIIδ) to promote mixed lineage kinase domain-like (MLKL) phosphorylation and necroptotic cell death. Furthermore, OSW-1-induced necroptosis is highly immunogenic and sensitizes syngeneic colorectal tumors to anti-PD-1 immunotherapy. Together, our results identified a novel RIP1/RIP3-independent necroptosis pathway underlying the extremely potent anticancer activity of OSW-1, which can be harnessed to develop new anticancer therapies by selectively stimulating antitumor immunity.
氧化甾醇结合蛋白（OSBPs）是在细胞内膜接触位点发挥作用的脂质转运蛋白，最近发现其在癌症中失调并促进癌细胞存活。然而，它们作为癌症治疗潜在靶点的作用在很大程度上仍未得到探索。在本研究中，我们发现天然化合物OSW-1作为一种OSBP抑制剂，通过激活一条先前未知的坏死性凋亡途径，有效且选择性地杀死结肠癌细胞，该途径独立于受体相互作用蛋白1（RIP1）和RIP3。OSW-1使p53稳定并降解OSBPs，以促进内质网（ER）应激以及糖原合酶激酶3β（GSK3β）/Tip60介导的p53赖氨酸120位点乙酰化，从而选择性地诱导其靶点p53上调凋亡调节蛋白（PUMA）。PUMA介导的线粒体钙内流激活钙/钙调蛋白依赖性蛋白激酶IIδ（CamKIIδ），以促进混合谱系激酶结构域样蛋白（MLKL）磷酸化和坏死性凋亡细胞死亡。此外，OSW-1诱导的坏死性凋亡具有高度免疫原性，并使同基因结直肠肿瘤对抗程序性死亡蛋白1（PD-1）免疫疗法敏感。总之，我们的结果确定了一条新的独立于RIP1/RIP3的坏死性凋亡途径，该途径是OSW-1极强抗癌活性的基础，可通过选择性刺激抗肿瘤免疫来开发新的抗癌疗法。
