Fei Yinjiao, Yan Xueqin, Liang Mingxing, Zhou Shu, Xu Di, Li Lei, Xu Weilin, Song Yuxin, Zhu Zhen, Zhang Jian
Department of Radiation Therapy, the First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China.
Department of General Surgery, the First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China.
Cancer Cell Int. 2024 Dec 3;24(1):394. doi: 10.1186/s12935-024-03579-9.
Breast cancer remains the most prevalent malignancy in women. Chemotherapy is the primary systemic treatment modality, and the effectiveness of treatment is often hampered by chemoresistance. Autophagy has been implicated in promoting chemoresistance, as elevated autophagic flux supports tumor cell survival under therapeutic stress. Since lysosomes are essential for the completion of autophagy, their role in autophagy-related chemoresistance has been insufficiently studied. This study aims to elucidate the role of the lysosomal gene ATP6AP1 in promoting chemoresistance in breast cancer by upregulating autophagic flux.
Doxorubicin-induced cell death was assessed by cytotoxicity, flow cytometry, lactate dehydrogenase (LDH) release assays in various breast cancer cell lines. Autophagic flux was assessed with western blot and the mRFP-GFP-LC3 fluorescence imaging. Breast cancer cells were infected with shRNA lentivirus targeting ATP6AP1, allowing investigation its tole in doxorubicin-induced cell death. ATP6AP1 expression and its association with prognosis were evaluated using public databases and immunohistochemistry.
Doxorubicin-induced cell death in breast cancer cells is negatively correlated with increased autophagic flux and lysosomal acidification. The lysosomal gene ATP6AP1, which plays a role in autophagic processes, is upregulated in breast cancer tissues. Knocking down ATP6AP1 reduces autophagy-mediated doxorubicin resistance by inhibiting autophagic flux and lysosomal acidification in breast cancer cells. Data analysis from public databases and our cohort indicate that elevated ATP6AP1 expression correlates with poor response to doxorubicin-based neoadjuvant chemotherapy (NAC) and worse prognosis.
Doxorubicin-induced cytotoxicity is associated with autophagy flux in breast cancer. The lysosomal gene ATP6AP1 facilitates autolysosome acidification and contributes to doxorubicin resistance in breast cancer.
乳腺癌仍是女性中最常见的恶性肿瘤。化疗是主要的全身治疗方式，而化疗耐药常常阻碍治疗效果。自噬被认为与化疗耐药的发生有关，因为自噬通量的增加有助于肿瘤细胞在治疗压力下存活。由于溶酶体对于自噬的完成至关重要，其在自噬相关化疗耐药中的作用尚未得到充分研究。本研究旨在阐明溶酶体基因ATP6AP1通过上调自噬通量在促进乳腺癌化疗耐药中的作用。
通过细胞毒性、流式细胞术、乳酸脱氢酶（LDH）释放试验评估阿霉素诱导的各种乳腺癌细胞系中的细胞死亡情况。采用蛋白质免疫印迹法和mRFP-GFP-LC3荧光成像评估自噬通量。用靶向ATP6AP1的短发夹RNA慢病毒感染乳腺癌细胞，以研究其在阿霉素诱导的细胞死亡中的作用。使用公共数据库和免疫组织化学评估ATP6AP1的表达及其与预后的关系。
阿霉素诱导的乳腺癌细胞死亡与自噬通量增加和溶酶体酸化呈负相关。在自噬过程中起作用的溶酶体基因ATP6AP1在乳腺癌组织中上调。敲低ATP6AP1可通过抑制乳腺癌细胞中的自噬通量和溶酶体酸化来降低自噬介导的阿霉素耐药性。来自公共数据库和我们队列的数据分析表明，ATP6AP1表达升高与基于阿霉素的新辅助化疗（NAC）反应不佳和预后较差相关。
阿霉素诱导的细胞毒性与乳腺癌中的自噬通量有关。溶酶体基因ATP6AP1促进自噬溶酶体酸化并导致乳腺癌中的阿霉素耐药。
