State Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
Cell Death Dis. 2024 Aug 21;15(8):605. doi: 10.1038/s41419-024-06989-9.
Intercellular cell adhesion molecule-1 (ICAM-1) is frequently overexpressed in non-small cell lung cancer (NSCLC) and associated with poor prognosis. However, the mechanism underlying the negative effects of neoplastic ICAM-1 remains obscure. Herein, we demonstrate that the survival of NSCLC cells but not normal human bronchial epithelial cells requires an anti-apoptosis signal triggered by fibrinogen γ chain (FGG)-ICAM-1 interaction. ICAM-1-FGG ligation preserves the tyrosine phosphorylation of ICAM-1 cytoplasmic domain and its association with SHP-2, and subsequently promotes Akt and ERK1/2 activation but suppresses JNK and p38 activation. Abolishing ICAM-1-FGG interaction induces NSCLC cell death by activating caspase-9/3 and significantly inhibits tumor development in a mouse xenograft model. Finally, we developed a monoclonal antibody against ICAM-1-FGG binding motif, which blocks ICAM-1‒FGG interaction and effectively suppresses NSCLC cell survival in vitro and tumor growth in vivo. Thus, suppressing ICAM-1-FGG axis provides a potential strategy for NSCLC targeted therapy.
细胞间黏附分子-1（ICAM-1）在非小细胞肺癌（NSCLC）中常过度表达，并与不良预后相关。然而，肿瘤 ICAM-1 产生负面影响的机制尚不清楚。在此，我们证明了纤维蛋白原 γ 链（FGG）-ICAM-1 相互作用触发的抗细胞凋亡信号对于 NSCLC 细胞的存活是必需的，但对正常的人支气管上皮细胞则不然。ICAM-1-FGG 连接保持了 ICAM-1 胞质结构域的酪氨酸磷酸化及其与 SHP-2 的结合，随后促进 Akt 和 ERK1/2 的激活，但抑制 JNK 和 p38 的激活。通过激活 caspase-9/3，消除 ICAM-1-FGG 相互作用可诱导 NSCLC 细胞死亡，并在小鼠异种移植模型中显著抑制肿瘤的发展。最后，我们开发了一种针对 ICAM-1-FGG 结合基序的单克隆抗体，该抗体可阻断 ICAM-1-FGG 相互作用，有效地抑制 NSCLC 细胞在体外的存活和体内的肿瘤生长。因此，抑制 ICAM-1-FGG 轴为 NSCLC 的靶向治疗提供了一种潜在策略。
