Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Guangdong Province Key Laboratory of Molecular Tumor Pathology, Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Cancer Lett. 2023 Nov 1;576:216420. doi: 10.1016/j.canlet.2023.216420. Epub 2023 Sep 29.
LIM kinase 1 (LIMK1) is a member of the LIMK family that has been considered to be involved in chemoresistance in various tumors, and N-methyladenosine (mA) is the most abundant nucleotide modification on mRNA. However, whether elevated expression of LIMK1 leads to chemoresistance due to mA modification remains to be further studied. The findings of our study indicate that high LIMK1 expression in colorectal cancer (CRC) cells promotes cell proliferation and increases resistance to 5-fluorouracil (5-FU). Moreover, downregulation of YTH domain-containing 2 (YTHDC2), an mA "reader", in CRC cells resulted in decreased recognition and binding to the mA site "GGACA" in LIMK1 mRNA, thereby increasing LIMK1 mRNA stability and expression. Furthermore, the overexpression of LIMK1 facilitated eIF2α phosphorylation, which induced endoplasmic reticulum (ER) stress and promoted stress granule (SG) formation, ultimately leading to 5-FU resistance. This study evaluated the specificity of the YTHDC2/LIMK1/eIF2α signalling axis and the efficacy of related drugs in modulating 5-FU sensitivity in CRC.
LIM 激酶 1（LIMK1）是 LIMK 家族的一员，被认为参与了多种肿瘤的化疗耐药性，N6-甲基腺苷（m6A）是 mRNA 上最丰富的核苷酸修饰。然而，LIMK1 的高表达是否由于 mA 修饰导致化疗耐药性仍有待进一步研究。我们的研究结果表明，结直肠癌细胞（CRC）中高表达 LIMK1 促进细胞增殖，并增加对 5-氟尿嘧啶（5-FU）的耐药性。此外，CRC 细胞中 YTH 结构域包含蛋白 2（YTHDC2）下调，一种 mA“读取器”，导致 LIMK1 mRNA 中 mA 位点“GGACA”的识别和结合减少，从而增加 LIMK1 mRNA 的稳定性和表达。此外，LIMK1 的过表达促进了真核起始因子 2α（eIF2α）的磷酸化，诱导内质网（ER）应激，促进应激颗粒（SG）形成，最终导致 5-FU 耐药性。本研究评估了 YTHDC2/LIMK1/eIF2α 信号通路的特异性以及相关药物在调节 CRC 中 5-FU 敏感性方面的疗效。
