Department of Experimental Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
Mol Med Rep. 2021 May;23(5). doi: 10.3892/mmr.2021.11999. Epub 2021 Mar 24.
Chaperone‑mediated autophagy (CMA) is a selective type of autophagy whereby a specific subset of intracellular proteins is targeted to the lysosome for degradation. The present study investigated the mechanisms underlying the response and resistance to 5‑fluorouracil (5‑FU) in colorectal cancer (CRC) cell lines. In engineered 5‑FU‑resistant CRC cell lines, a significant elevation of lysosome‑associated membrane protein 2A (LAMP2A), which is the key molecule in the CMA pathway, was identified. High expression of LAMP2A was found to be responsible for 5‑FU resistance and to enhance PLD2 expression through the activation of NF‑κB pathway. Accordingly, loss or gain of function of LAMP2A in 5‑FU‑resistant CRC cells rendered them sensitive or resistant to 5‑FU, respectively. Taken together, the results of the present study suggested that chemoresistance in patients with CRC may be mediated by enhancing CMA. Thus, CMA is a promising predictor of chemosensitivity to 5‑FU treatment and anti‑CMA therapy may be a novel therapeutic option for patients with CRC.
伴侣蛋白介导的自噬（CMA）是一种选择性的自噬形式，其中特定的细胞内蛋白质被靶向到溶酶体进行降解。本研究探讨了结直肠癌细胞系对 5-氟尿嘧啶（5-FU）的反应和耐药机制。在工程化的 5-FU 耐药结直肠癌细胞系中，鉴定到溶酶体相关膜蛋白 2A（LAMP2A）的显著升高，LAMP2A 是 CMA 途径中的关键分子。高表达的 LAMP2A 被发现负责 5-FU 耐药，并通过 NF-κB 通路的激活增强 PLD2 的表达。因此，在 5-FU 耐药结直肠癌细胞中敲低或过表达 LAMP2A 分别使它们对 5-FU 敏感或耐药。总之，本研究的结果表明，CRC 患者的化疗耐药可能是通过增强 CMA 介导的。因此，CMA 是对 5-FU 治疗敏感性的有前途的预测因子，抗 CMA 治疗可能是 CRC 患者的一种新的治疗选择。
