EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1-TUFM protein complex.
EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1-TUFM protein complex.
复制标题
EGFR靶向的MAB疗法通过NLRX1-TUFM蛋白复合物调节头部和颈部鳞状细胞癌的自噬调节。
DOI：
10.1038/onc.2016.11
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发表时间：
2016-09-08
期刊：
影响因子：
8
通讯作者：
Ferris RL
中科院分区：
文献类型：
--
作者：
Lei Y;Kansy BA;Li J;Cong L;Liu Y;Trivedi S;Wen H;Ting JP;Ouyang H;Ferris RL
头颈鳞状细胞癌 (HNSCC) 患者的 EGFR 靶向治疗经常导致肿瘤对治疗产生耐药性。自噬是一种新兴的潜在耐药机制，然而，HNSCC 细胞中的分子自噬机制和患者对 EGFR 靶向治疗反应的潜在生物标志物的特征仍不充分。在这里，我们表明用西妥昔单抗阻断 EGFR 会导致不同的自噬反应，从而调节癌细胞对 EGFR 抑制的敏感性。自噬的抑制使 HNSCC 细胞对 EGFR 阻断敏感。重要的是，我们发现了一种以 NLRX1-TUFM 蛋白复合物为中心的新型信号中枢，可促进自噬通量。当使用 EGFR 抑制剂治疗时，NLRX1 或 TUFM 的表达缺陷会导致自噬受损。作为一种先前未定义的自噬促进机制，我们发现 TUFM 作为一种新的锚定位点，将 Beclin-1 招募到线粒体，促进其多泛素化，并干扰其与 Rubicon 的相互作用。这种蛋白质复合物对于内质网 (ER) 应激信号传导也至关重要，可能作为促进自噬的额外机制。利用来自一项新型新辅助临床试验的肿瘤标本，我们发现自噬接头蛋白 SQSTM1/p62 表达的增加与西妥昔单抗治疗的不良反应相关。这些发现扩展了我们对 HNSCC 自噬机制中参与 EGFR 抑制剂反应的成分的理解，并提出了增强其治疗功效的潜在组合方法。
EGFR-targeted therapy in head and neck squamous cell carcinoma (HNSCC) patients frequently results in tumor resistance to treatment. Autophagy is an emerging underlying resistance mechanism, however, the molecular autophagy machinery in HNSCC cells and potential biomarkers of patient response to EGFR-targeted therapy remain insufficiently characterized. Here we show that the EGFR blocking with cetuximab leads to varied autophagic responses, which modulate cancer cell susceptibility to EGFR inhibition. Inhibition of autophagy sensitizes HNSCC cells to EGFR blockade. Importantly, we identify a novel signaling hub centering on the NLRX1-TUFM protein complex, promoting autophagic flux. Defects in the expression of either NLRX1 or TUFM result in compromised autophagy when treated with EGFR inhibitors. As a previously undefined autophagy-promoting mechanism, we found that TUFM serves as a novel anchorage site, recruiting Beclin-1 to mitochondria, promoting its polyubiquitination, and interfering with its interaction with Rubicon. This protein complex is also essential for endoplasmic reticulum (ER) stress signaling induction, possibly as an additional mechanism to promote autophagy. Utilizing tumor specimens from a novel neoadjuvant clinical trial, we show that increased expression of the autophagy adaptor protein, SQSTM1/p62, is associated with poor response to cetuximab therapy. These findings expand our understanding of the components involved in HNSCC autophagy machinery that responds to EGFR inhibitors, and suggest potential combinatorial approaches to enhance its therapeutic efficacy.