Department of Surgery, University Hospitals; Case Western University, School of Medicine, Cleveland, OH.
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX.
Cancer Res Commun. 2021 Nov;1(2):65-78. doi: 10.1158/2767-9764.crc-21-0073.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis and chemotherapy with gemcitabine has limited effects and is associated with development of drug resistance. Treatment of Panc1 and MiaPaca2 pancreatic cancer cells with gemcitabine induced expression of the orphan nuclear receptor 4A2 (NURR1) and analysis of the cancer genome atlas indicated the NURR1 is overexpressed in pancreatic tumors and is a negative prognostic factor for patient survival. Results of NURR1 knockdown or treatment with the NURR1 antagonist 1,1-bis(3΄-indolyl)-1-(p-chlorophenyl)methane (C-DIM 12) demonstrated that NURR1 was pro-oncogenic in pancreatic cancer cells and regulated cancer cell and tumor growth and survival. NURR1 is induced by gemcitabine and serves as a key drug-resistance factor and is also required for gemcitabine-induced cytoprotective autophagy. NURR1 regulated genes were determined by RNA sequencing of mRNAs expressed in MiaPaCa2 cells expressing NURR1 and in CRISPR/Cas9 gene edited cells for NURR1 knockdown and KEGG enrichment analysis of the differentially expressed genes showed that autophagy was the major pathway regulated by NURR1. Moreover, NURR1 regulated expression of two major autophagic genes ATG7 and ATG12 which are also overexpressed in pancreatic tumors and like NURR1 are negative prognostic factors for patient survival. Thus, gemcitabine-induced cytoprotective autophagy is due to the NURR1 - ATG7/ATG12 axis and this can be targeted and disrupted by NURR1 antagonist C-DIM12 demonstrating the potential clinical applications for combination therapies with gemcitabine and NURR1 antagonists.
胰腺导管腺癌（PDAC）是一种侵袭性很强的癌症，预后较差，吉西他滨化疗效果有限，且与耐药性的发展有关。用吉西他滨处理 Panc1 和 MiaPaca2 胰腺癌细胞会诱导孤儿核受体 4A2（NURR1）的表达，并且癌症基因组图谱分析表明 NURR1 在胰腺肿瘤中过表达，并且是患者生存的负预后因素。NURR1 敲低或用 NURR1 拮抗剂 1,1-双（3′-吲哚基）-1-（对氯苯基）甲（C-DIM 12）处理的结果表明，NURR1 在胰腺癌细胞中具有致癌作用，并调节癌细胞和肿瘤的生长和存活。NURR1 由吉西他滨诱导，是关键的耐药因素，也是吉西他滨诱导的细胞保护性自噬所必需的。通过 MiaPaCa2 细胞中表达 NURR1 的 mRNA 的 RNA 测序和用于 NURR1 敲低的 CRISPR/Cas9 基因编辑细胞确定 NURR1 调节的基因，并对差异表达基因进行 KEGG 富集分析表明，自噬是 NURR1 主要调节的途径。此外，NURR1 调节两个主要自噬基因 ATG7 和 ATG12 的表达，这两个基因在胰腺肿瘤中也过表达，与 NURR1 一样，是患者生存的负预后因素。因此，吉西他滨诱导的细胞保护性自噬是由于 NURR1-ATG7/ATG12 轴，并且可以通过 NURR1 拮抗剂 C-DIM12 靶向和破坏该轴，这表明与吉西他滨和 NURR1 拮抗剂联合治疗的潜在临床应用。
