矩阵刚度已被证明在癌症进展中发挥着关键作用，通过影响多种细胞过程，包括上皮生长因子（EGF）信号传导。然而，其潜在的分子机制尚未完全理解。在本研究中，我们调查了适配器相关蛋白复合物1亚单位sigma 1（AP1S1），即适配器蛋白复合物-1的一个组分，在癌症细胞进展中调控EGF受体（EGFR）胞内转运的作用。我们发现在坚硬的基质条件下AP1S1表达上调，从而调节非小细胞肺腺癌细胞中的EGFR转运。AP1S1敲除导致EGFR的溶酶体降解，从而抑制EGF诱导的间变性淋巴瘤受体酪氨酸激酶磷酸化。此外，AP1S1的下调增加了H1975癌细胞对酪氨酸激酶抑制剂依罗替尼的敏感性，后者对其具有抗药性。综上所述，我们的结果表明AP1S1可以在坚硬的基质条件下调控EGFR的再循环，并且AP1S1的抑制可能是治疗对EGFR靶向抗癌药物具有耐药性的癌细胞的一种新策略。©2023 Wiley Periodicals LLC.

Matrix stiffness has been shown to play a critical role in cancer progression by influencing various cellular processes, including epidermal growth factor (EGF) signaling. However, the underlying molecular mechanisms are not fully understood. Here, we investigated the role of adaptor-related protein complex 1 subunit sigma 1 (AP1S1), a component of adaptor protein complex-1, in the regulation of EGF receptor (EGFR) intracellular trafficking during cancer cell progression. We found that AP1S1 expression was upregulated under stiff matrix conditions, resulting in the regulation of EGFR trafficking in non-small cell lung adenocarcinoma cells. Knockout of AP1S1 caused the lysosomal degradation of EGFR, leading to suppressed EGF-induced anaplastic lymphoma receptor tyrosine kinase phosphorylation. In addition, the downregulation of AP1S1 increased the sensitivity of H1975 cancer cells, which are resistant to tyrosine kinase inhibitors, to erlotinib. Collectively, our results suggest that AP1S1 could regulate EGFR recycling under stiff matrix conditions, and AP1S1 inhibition could be a novel strategy for treating cancer cells resistant to EGFR-targeted anticancer drugs.© 2023 Wiley Periodicals LLC.