Targeting ENPP1 depletion may be a promising therapeutic strategy for treating oral squamous cell carcinoma via cytotoxic autophagy-related apoptosis
Targeting ENPP1 depletion may be a promising therapeutic strategy for treating oral squamous cell carcinoma via cytotoxic autophagy-related apoptosis
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DOI：
10.1096/fj.202301835r
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发表时间：
2024-01-31
期刊：
影响因子：
4.8
通讯作者：
Zhang，Tao
中科院分区：
文献类型：
--
作者：
Ma，Chao;Zhao，Jizhi;Zhang，Tao
ENPP 1缺失与多种肿瘤的免疫调节治疗密切相关。然而，ENPP 1与自噬在口腔鳞状细胞癌（OSCC）发病机制中的作用尚不清楚。本研究采用细胞增殖实验、transwell小室实验、流式细胞仪分析和shRNA技术检测ENPP 1对体外培养的口腔鳞癌细胞的影响。Western blot和免疫荧光染色检测与细胞自噬和凋亡相关的关键蛋白。并在裸鼠口腔鳞癌模型上观察ENPP 1在口腔鳞癌发生发展过程中的作用。我们报道过表达ENPP 1可促进口腔鳞癌细胞裸鼠移植瘤的生长。相反，ENPP 1下调显著抑制OSCC癌生长，并在体外和体内诱导细胞凋亡，这之前是细胞毒性自噬。ENPP 1下调诱导自噬体的稳健积累，增加ENPP 1-shRNA处理的细胞和异种移植物中的LC 3B-II并降低SQSTM 1/p62。机制研究表明，ENPP 1下调增加PRKAA 1磷酸化，导致ULK 1活化。AMPK-抑制消除ENPP 1下调诱导的ULK 1-活化，LC 3B-周转和SQSTM 1/p62-降解，而AMPK-活化增强其作用。总的来说，这些数据揭示了ENPP 1下调诱导OSCC癌中的自噬性细胞死亡，这可能为OSCC的治疗提供潜在的治疗靶点。
ENPP1 depletion closely related with modulation immunotherapy of several types of cancer. However, the role of ENPP1 correlation with autophagy in oral squamous cell carcinoma (OSCC) pathogenesis remain unknown. In this study, effects of ENPP1 on OSCC cells in vitro were examined by cell proliferation assay, transwell chamber assay, flow cytometry analysis and shRNA technique. Cellular key proteins related to cell autophagy and apoptosis were evaluated by Western blot and immunofluorescent staining. Moreover, functions of ENPP1 on OSCC process were observed in nude mouse model. We reported that overexpression of ENPP1 promote the growth of OSCC cell xenografts in nude mouse model. In contrast, ENPP1 downregulation significantly inhibits OSCC cancer growth and induces apoptosis both in vitro and in vivo, which are preceded by cytotoxic autophagy. ENPP1downregulation induces a robust accumulation of autophagosomes, increases LC3B‐II and decreases SQSTM1/p62 in ENPP1‐shRNA‐treated cells and xenografts. Mechanistic studies show that ENPP1 downregulation increases PRKAA1 phosphorylation leading to ULK1 activation. AMPK‐inhibition abrogates ENPP1 downregulation‐induced ULK1‐activation, LC3B‐turnover and SQSTM1/p62‐degradation while AMPK‐activation potentiates it's effects. Collectively, these data uncover that ENPP1 downregulation induces autophagic cell death in OSCC cancer, which may provide a potential therapeutic target for the treatment of OSCC.