Department of Radiation Oncology, Stanford University School of Medicine, Palo Alto, CA 94304, USA; Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Palo Alto, CA 94304, USA; Department of Cell, Development and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA.
Department of Radiation Oncology, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
Cell Chem Biol. 2021 Aug 19;28(8):1206-1220.e6. doi: 10.1016/j.chembiol.2021.02.014. Epub 2021 Mar 12.
Y box binding protein 1 (YB-1) is a multifunctional protein associated with tumor progression and the emergence of treatment resistance (TR). Here, we report an azopodophyllotoxin small molecule, SU056, that potently inhibits tumor growth and progression via YB-1 inhibition. This YB-1 inhibitor inhibits cell proliferation, resistance to apoptosis in ovarian cancer (OC) cells, and arrests in the G1 phase. Inhibitor treatment leads to enrichment of proteins associated with apoptosis and RNA degradation pathways while downregulating spliceosome pathway. In vivo, SU056 independently restrains OC progression and exerts a synergistic effect with paclitaxel to further reduce disease progression with no observable liver toxicity. Moreover, in vitro mechanistic studies showed delayed disease progression via inhibition of drug efflux and multidrug resistance 1, and significantly lower neurotoxicity as compared with etoposide. These data suggest that YB-1 inhibition may be an effective strategy to reduce OC progression, antagonize TR, and decrease patient mortality.
Y 盒结合蛋白 1（YB-1）是一种与肿瘤进展和治疗抵抗（TR）出现相关的多功能蛋白。在这里，我们报告了一种吖泊podophyllotoxin 小分子 SU056，它通过抑制 YB-1 来有力地抑制肿瘤生长和进展。这种 YB-1 抑制剂抑制卵巢癌（OC）细胞的增殖、抗细胞凋亡，并将细胞周期阻滞在 G1 期。抑制剂处理导致与细胞凋亡和 RNA 降解途径相关的蛋白质富集，同时下调剪接体途径。在体内，SU056 独立地抑制 OC 的进展，并与紫杉醇产生协同作用，进一步减少疾病进展，而没有观察到肝毒性。此外，体外机制研究表明，通过抑制药物外排和多药耐药蛋白 1，疾病进展延迟，与依托泊苷相比，神经毒性显著降低。这些数据表明，YB-1 抑制可能是减少 OC 进展、拮抗 TR 和降低患者死亡率的有效策略。
