Lester and Sue Smith Breast Center, and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
Department of Oncology and Hematology, Hospital (TCM) Affiliated to Southwest Medical University, Luzhou, Sichuan, 646000, P. R. China.
Sci Rep. 2018 Nov 16;8(1):16932. doi: 10.1038/s41598-018-35237-2.
Ras GTPases are powerful drivers for tumorigenesis, but directly targeting Ras for treating cancer remains challenging. The growth and transforming activity of the aggressive basal-like breast cancer (BLBC) are driven by N-Ras. To target N-Ras in BLBC, this study screened existing pharmacologically active compounds for the new ability to induce N-Ras degradation, which led to the identification of flunarizine (FLN), previously approved for treating migraine and epilepsy. The FLN-induced N-Ras degradation was not affected by a 26S-proteasome inhibitor. Rather, it was blocked by autophagy inhibitors. Furthermore, N-Ras can be seen co-localized with active autophagosomes upon FLN treatment, suggesting that FLN alters the autophagy pathway to degrade N-Ras. Importantly, FLN treatment recapitulated the effect of N-RAS silencing in vitro by selectively inhibiting the growth of BLBC cells, but not that of breast cancer cells of other subtypes. In addition, in vivo FLN inhibited tumor growth of a BLBC xenograft model. In conclusion, this proof-of-principle study presents evidence that the autophagy pathway can be coerced by small molecule inhibitors, such as FLN, to degrade Ras as a strategy to treat cancer. FLN has low toxicity and should be further investigated to enrich the toolbox of cancer therapeutics.
Ras GTPases 是肿瘤发生的强大驱动因素，但直接针对 Ras 治疗癌症仍然具有挑战性。侵袭性基底样乳腺癌（BLBC）的生长和转化活性受 N-Ras 驱动。为了在 BLBC 中靶向 N-Ras，本研究筛选了现有的具有诱导 N-Ras 降解新能力的药理活性化合物，从而鉴定出先前被批准用于治疗偏头痛和癫痫的氟桂利嗪（FLN）。FLN 诱导的 N-Ras 降解不受 26S 蛋白酶体抑制剂的影响。相反，它被自噬抑制剂阻断。此外，FLN 处理后可以看到 N-Ras 与活跃的自噬体共定位，表明 FLN 改变了自噬途径以降解 N-Ras。重要的是，FLN 治疗通过选择性抑制 BLBC 细胞的生长，而不是其他亚型乳腺癌细胞的生长，再现了 N-RAS 沉默在体外的效果。此外，体内 FLN 抑制了 BLBC 异种移植模型的肿瘤生长。总之，这项原理验证研究提供了证据表明，自噬途径可以被小分子抑制剂（如 FLN）强迫降解 Ras，作为治疗癌症的一种策略。FLN 毒性低，应进一步研究以丰富癌症治疗的工具包。
