Duksung Innovative Drug Center, College of Pharmacy, Duksung Women's University, Seoul, Korea.
Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
Autophagy. 2024 Mar;20(3):659-674. doi: 10.1080/15548627.2024.2305063. Epub 2024 Jan 30.
Triple-negative breast cancer (TNBC) is associated with a poor prognosis and metastatic growth. TNBC cells frequently undergo macroautophagy/autophagy, contributing to tumor progression and chemotherapeutic resistance. ANXA2 (annexin A2), a potential therapeutic target for TNBC, has been reported to stimulate autophagy. In this study, we investigated the role of ANXA2 in autophagic processes in TNBC cells. TNBC patients exhibited high levels of ANXA2, which correlated with poor outcomes. ANXA2 increased LC3B-II levels following bafilomycin A treatment and enhanced autophagic flux in TNBC cells. Notably, ANXA2 upregulated the phosphorylation of HSF1 (heat shock transcription factor 1), resulting in the transcriptional activation of (autophagy related 7). The mechanistic target of rapamycin kinase complex 2 (MTORC2) played an important role in ANXA2-mediated transcription by HSF1. MTORC2 did not affect the mRNA level of , but it was involved in the protein stability of ANXA2. HSPA (heat shock protein family A (Hsp70)) was a potential interacting protein with ANXA2, which may protect ANXA2 from lysosomal proteolysis. ANXA2 knockdown significantly increased sensitivity to doxorubicin, the first-line chemotherapeutic regimen for TNBC treatment, suggesting that the inhibition of autophagy by ANXA2 knockdown may overcome doxorubicin resistance. In a TNBC xenograft mouse model, we demonstrated that ANXA2 knockdown combined with doxorubicin administration significantly inhibited tumor growth compared to doxorubicin treatment alone, offering a promising avenue to enhance the effectiveness of chemotherapy. In summary, our study elucidated the molecular mechanism by which ANXA2 modulates autophagy, suggesting a potential therapeutic approach for TNBC treatment. ATG: autophagy related; ChIP: chromatin-immunoprecipitation; HBSS: Hanks' balanced salt solution; HSF1: heat shock transcription factor 1; MTOR: mechanistic target of rapamycin kinase; TNBC: triple-negative breast cancer; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3.
三阴性乳腺癌（TNBC）与预后不良和转移性生长有关。TNBC 细胞经常经历巨自噬/自噬，促进肿瘤进展和化疗耐药。ANXA2（膜联蛋白 A2）是 TNBC 的潜在治疗靶点，已被报道刺激自噬。在这项研究中，我们研究了 ANXA2 在 TNBC 细胞自噬过程中的作用。TNBC 患者表现出高水平的 ANXA2，这与不良结局相关。ANXA2 在巴弗洛霉素 A 处理后增加 LC3B-II 水平，并增强 TNBC 细胞的自噬流。值得注意的是，ANXA2 上调 HSF1（热休克转录因子 1）的磷酸化，导致 （自噬相关 7）的转录激活。雷帕霉素激酶复合物 2（MTORC2）的机械靶标在 ANXA2 介导的 HSF1 转录中发挥重要作用。MTORC2 不影响 的 mRNA 水平，但它参与 ANXA2 的蛋白稳定性。HSPA（热休克蛋白家族 A（Hsp70））是与 ANXA2 相互作用的潜在蛋白，可能保护 ANXA2 免受溶酶体蛋白水解。ANXA2 敲低显著增加了对多柔比星的敏感性，多柔比星是 TNBC 治疗的一线化疗方案，表明通过 ANXA2 敲低抑制自噬可能克服多柔比星耐药性。在 TNBC 异种移植小鼠模型中，我们证明与单独多柔比星治疗相比，ANXA2 敲低联合多柔比星给药显著抑制肿瘤生长，为增强化疗效果提供了有前途的途径。总之，我们的研究阐明了 ANXA2 调节自噬的分子机制，为 TNBC 治疗提供了一种潜在的治疗方法。ATG：自噬相关；ChIP：染色质免疫沉淀；HBSS：汉克斯平衡盐溶液；HSF1：热休克转录因子 1；MTOR：雷帕霉素激酶；TNBC：三阴性乳腺癌；TFEB：转录因子 EB；TFE3：转录因子结合 IGHM 增强子 3。
