众所周知，三阴性乳腺癌的雌激素、孕激素、HER2三大受体均为阴性，故抗激素和抗HER2的靶向药物疗效不佳，目前药物治疗主要依靠化疗，但是化疗耐药、癌症转移的比例仍然居高不下。Wnt→β联蛋白信号传导活化的失控，对于三阴性乳腺癌等恶性肿瘤生长、转移、耐药具有关键作用。多柔比星、卡铂、伊立替康等基因毒性化疗药物，已被证实可以激活Wnt→β联蛋白信号传导，不过其具体机制尚不明确。
2020年8月7日，英国《自然》旗下《自然通讯》在线发表美国田纳西大学健康科学中心吴朝晖、中国复旦大学附属肿瘤医院迟亚云、薛静彦、吴炅等学者的研究报告，探讨了基因毒性化疗药物激活Wnt→β联蛋白信号传导的具体机制和临床意义。
该研究发现，基因毒性化疗药物可以直接激活Wnt→β联蛋白信号传导，而不需要依赖于Wnt信号传导通路的卷曲受体→低密度脂蛋白受体相关蛋白异二聚体受体和Wnt配体。
其中，线性连接特异去泛素酶OTULIN对于DNA损伤诱发β联蛋白活化至关重要。OTULIN可以抑制β联蛋白的线性泛素化，从而减弱其第48位赖氨酸相关泛素化和DNA损伤后蛋白酶体降解。被基因毒性化疗药物激活的酪氨酸蛋白激酶ABL1将OTULIN第56位酪氨酸磷酸化，可以增强其与β联蛋白的结合。
此外，利用靶向药物抑制OTULIN或Wnt→β联蛋白信号传导，可使三阴性乳腺癌异种移植肿瘤对化疗药物敏感并减少转移。
而且，OTULIN水平升高与乳腺癌的高度恶性分子亚型和患者不良生存结局显著相关。
因此，该研究结果表明，基因毒性化疗药物治疗引起OTULIN被ABL1磷酸化从而激活Wnt→β联蛋白信号传导，可以促进三阴性乳腺癌耐药和转移。利用靶向药物抑制OTULIN或Wnt→β联蛋白信号传导，可使三阴性乳腺癌对化疗药物敏感并减少转移，故有必要进一步开展临床研究进行验证。
Nat Commun. 2020 Aug 7;11(1):3965.
ABL1-dependent OTULIN phosphorylation promotes genotoxic Wnt/β-catenin activation to enhance drug resistance in breast cancers.
Wang W, Li M, Ponnusamy S, Chi Y, Xue J, Fahmy B, Fan M, Miranda-Carboni GA, Narayanan R, Wu J, Wu ZH.
University of Tennessee Health Science Center, Memphis, TN, USA; Fudan University Shanghai Cancer Center, Shanghai, China.
Dysregulated Wnt/β-catenin activation plays a critical role in cancer progression, metastasis, and drug resistance. Genotoxic agents such as radiation and chemotherapeutics have been shown to activate the Wnt/β-catenin signaling although the underlying mechanism remains incompletely understood. Here, we show that genotoxic agent-activated Wnt/β-catenin signaling is independent of the FZD/LRP heterodimeric receptors and Wnt ligands. OTULIN, a linear linkage-specific deubiquitinase, is essential for the DNA damage-induced β-catenin activation. OTULIN inhibits linear ubiquitination of β-catenin, which attenuates its Lys48-linked ubiquitination and proteasomal degradation upon DNA damage. The association with β-catenin is enhanced by OTULIN Tyr56 phosphorylation, which depends on genotoxic stress-activated ABL1/c-Abl. Inhibiting OTULIN or Wnt/β-catenin sensitizes triple-negative breast cancer xenograft tumors to chemotherapeutics and reduces metastasis. Increased OTULIN levels are associated with aggressive molecular subtypes and poor survival in breast cancer patients. Thus, OTULIN-mediated Wnt/β-catenin activation upon genotoxic treatments promotes drug resistance and metastasis in breast cancers.
PMID: 32770022
DOI: 10.1038/s41467-020-17770-9
联系客服
