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Abstract：
Triple-negative breast cancer (TNBC) cells are often resistant to FAS (CD95)-mediated apoptosis, but the underlying molecular mechanism(s) is not fully understood yet. Notably, the expression of the type II transmembrane protein, CD74, is correlated with chemotherapy-resistant and more invasive forms of cancers via unknown mechanisms. Here, we analyzed gene expression pattern of cancer patients and/or patient-derived xenograft (PDX) models and found that mRNA and protein levels of CD74 are highly expressed in TNBC and correlated with cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) properties. Mechanistically, we found that AKT activation is likely critical for maintaining CD74 expression and protein stability to favor its oncogenic functions. Physiologically, epidermal growth factor (EGF) along with CD74 could activate AKT signaling, likely through binding of phosphorylated AKT (S473) to CD74, whereas inhibition of AKT could impair stability of CD74. We also revealed that CD74 binds to FAS and interferes with the intrinsic signaling of FAS-mediated apoptosis. As such, selective targeting of the CD74/FAS complex using the AKT inhibitor along with the CD74-derived peptide could synergistically restore and activate FAS-mediated apoptosis. Therefore, our approach of mobilizing apoptosis pathways likely provides a rationale for TNBC treatment by targeting the CD74/FAS and CD74-AKT axes.
摘要：
三阴性乳腺癌（TNBC）细胞通常对FAS（CD95）介导的凋亡具有抗性，但潜在的分子机制还没有完全理解。值得注意的是,II型跨膜蛋白的表达，CD74通过未知的机制与化疗抗性和更具侵袭性的癌症形式相关。这里,我们分析了癌症患者和/或患者来源的异种移植(PDX)模型的基因表达模式,发现CD74的mRNA和蛋白水平在TNBC中高表达,并与肿瘤干细胞(CSCs)和上皮-间质转化(EMT)特性相关.机械上,我们发现AKT的激活可能对于维持CD74的表达和蛋白质稳定性以促进其致癌功能至关重要。生理学上,表皮生长因子（EGF）和CD74可以激活AKT信号，可能是通过磷酸化AKT（S473）与CD74结合，而抑制AKT可能会损害CD74的稳定性。我们还揭示了CD74与FAS结合并干扰FAS介导的细胞凋亡的内在信号传导。因此，使用AKT抑制剂和CD74衍生肽对CD74/FAS复合物的选择性靶向可以协同恢复和激活FAS介导的细胞凋亡。因此,我们动员细胞凋亡途径的方法可能为靶向CD74/FAS和CD74-AKT轴治疗TNBC提供了理论基础.
