Wang Jingchao, Huang Daoyuan, Nguyen Thu Anh Thai, Phan Liem Minh, Wei Wenyi, Rezaeian Abdol-Hossein
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Genome and Systems Biology Degree Program, College of Life Science, National Taiwan University, Taipei 10617, Taiwan.
Biology (Basel). 2024 Jun 28;13(7):481. doi: 10.3390/biology13070481.
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.
三阴性乳腺癌（TNBC）细胞通常对FAS（CD95）介导的凋亡具有抗性，但其潜在的分子机制尚未完全清楚。值得注意的是，II型跨膜蛋白CD74的表达通过未知机制与化疗抗性和更具侵袭性的癌症形式相关。在此，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中高度表达，并且与癌症干细胞（CSCs）和上皮-间质转化（EMT）特性相关。从机制上讲，我们发现AKT激活可能对于维持CD74表达和蛋白稳定性以促进其致癌功能至关重要。在生理上，表皮生长因子（EGF）与CD74一起可能通过磷酸化的AKT（S473）与CD74结合来激活AKT信号，而抑制AKT可能损害CD74的稳定性。我们还揭示了CD74与FAS结合并干扰FAS介导的凋亡的内在信号。因此，使用AKT抑制剂和CD74衍生肽选择性靶向CD74/FAS复合物可以协同恢复并激活FAS介导的凋亡。因此，我们激活凋亡途径的方法可能为通过靶向CD74/FAS和CD74-AKT轴治疗TNBC提供理论依据。
