Abstract：
Fhit protein expression is reduced in the majority of human tumors; moreover, its restoration both triggers apoptosis of cancer cells and suppresses tumor formation in a large number of preclinical models of cancers. In the following study, we observed that Fhit expression is significantly reduced in human melanoma cells, and their in vivo growth is blocked by a recombinant adenovirus carrying the FHIT gene. Importantly, we found here that Fhit physically interacts with Hsp90. Since Hsp90 is a chaperone with a crucial function in the conformational maturation and stabilization of C-Raf, we also investigated whether Fhit could interfere with the Hsp90/C-Raf protein complex in melanoma. Interestingly, the administration of the Hsp90 inhibitor 17-AAG, in combination with Fhit protein overexpression in melanoma cells, reacts synergistically to increase C-Raf ubiquitination and degradation. These data reveal Hsp90 as a novel interactor of Fhit and suggest that FHIT activity restoration could represent a helpful strategy for suppressing the oncogenic C-Raf pathway in the therapy of human melanoma.
摘要：
Fhit蛋白表达在大多数人类肿瘤中降低；此外，在大量的癌症临床前模型中，它的恢复既能触发癌细胞的凋亡，又能抑制肿瘤的形成。在接下来的研究中，我们观察到Fhit在人黑色素瘤细胞中的表达显著降低，它们的体内生长被携带FHIT基因的重组腺病毒阻断。重要的是,我们在这里发现Fhit与Hsp90物理相互作用。由于Hsp90是在C-Raf的构象成熟和稳定中起关键作用的伴侣，我们还研究了Fhit是否会干扰黑色素瘤中的Hsp90/C-Raf蛋白复合物.有趣的是,Hsp90抑制剂17-AAG的给药，结合黑色素瘤细胞中的Fhit蛋白过表达，协同反应以增加C-Raf泛素化和降解。这些数据揭示了Hsp90作为Fhit的新型相互作用因子，并表明FHIT活性恢复可能代表了在人类黑色素瘤治疗中抑制致癌C-Raf途径的有用策略。
