PDF(Pubmed)
Abstract：
Anoikis is a common programmed death for most of detached cells, but cancer cells can obtain anoikis resistance to facilitate their distant metastasis through the circulation system. Researches have indicated that enhanced autophagic flux accounts for the survival of many cancer cells under detached conditions. Targeting ATG4B, the key factor of autophagy progress, can inhibit cancer metastasis in vitro, but ATG4B-deficient mice are susceptible to many serious diseases, which indicates the potential uncontrolled side effects of direct targeting of ATG4B. In our recent research, we confirmed that ATG4B is a novel RNA binding protein in the gastric cancer (GC) cell. It interacts with circSPECC1 which consequently facilitates the liquid-liquid phase separation and ubiquitination of ATG4B. Additionally, the m6A reader ELAVL1 inhibits the expression of circSPECC1 to enhance the expression of ATG4B and anoikis resistance of GC cells. Further, we screened out an FDA-approved compound, lopinavir, to restore circSPECC1 abundance and suppress GC metastasis. In conclusion, our research identified a novel signal pathway (ELAVL1-circSPECC1-ATG4B-autophagy) to facilitate anoikis resistance and metastasis of GC cells and screened out a compound with clinical application potential to block this pathway, providing a novel strategy for the prevention of GC metastasis.
摘要：
Anoikis是大多数分离细胞常见的程序性死亡，但是癌细胞可以通过循环系统获得抗失巢凋亡性，以促进其远处转移。研究表明，增强的自噬通量是许多癌细胞在分离条件下存活的原因。瞄准ATG4B,自噬进展的关键因素，可以在体外抑制癌症转移，但是缺乏ATG4B的小鼠易受许多严重疾病的影响，这表明直接靶向ATG4B的潜在不受控制的副作用。在我们最近的研究中,我们证实ATG4B是胃癌（GC）细胞中一种新的RNA结合蛋白。它与circSPEC1相互作用，从而促进ATG4B的液-液相分离和泛素化。此外,m6A阅读器ELAVL1抑制circspec1的表达，以增强GC细胞的ATG4B表达和抗肛门凋亡。Further,我们筛选出一种FDA批准的化合物，洛匹那韦,恢复circSPEC1丰度并抑制GC转移。总之,我们的研究确定了一个新的信号通路（ELAVL1-circSPECC1-ATG4B-自噬），以促进GC细胞的失巢凋亡抵抗和转移，并筛选出具有临床应用潜力的化合物来阻断该通路，为预防GC转移提供了新的策略。
