Pan Hong, Sun Yue, Qian Li-Heng, Liao Ying-Na, Gai Yan-Zhi, Huo Yan-Miao, Li Zuo-Qing, Nie Hui-Zhen
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China.
Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Research (Wash D C). 2024 Feb 2;7:0300. doi: 10.34133/research.0300. eCollection 2024.
Ferroptosis, a nonapoptotic form of cell death, is an emerging potential therapeutic target for various diseases, including cancer. However, the role of ferroptosis in pancreatic cancer remains poorly understood. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor prognosis and chemotherapy resistance, attributed to its high Kirsten rats arcomaviral oncogene homolog mutation rate and severe nutritional deficits resulting from a dense stroma. Several studies have linked rat sarcoma (RAS) mutations to ferroptosis, suggesting that inducing ferroptosis may be an effective strategy against oncogenic RAS-bearing tumors. We investigated the role of Family With Sequence Similarity 60 Member A (FAM60A) in this study, a protein closely associated with a poor prognosis and highly expressed in PDAC and tumor tissue from Kras;Trp53; Pdx1-Cre mice, in regulating ferroptosis, tumor growth, and gemcitabine sensitivity in vitro and in vivo. Our results demonstrate that FAM60A regulates 3 essential metabolic enzymes, ACSL1/4 and GPX4, to protect PDAC cells from ferroptosis. Furthermore, we found that YY1 transcriptionally regulates FAM60A expression by promoting its transcription, and the Hippo-YY1 pathway is restricted in the low-amino-acid milieu in the context of nutrient deprivation, leading to downstream suppression of peroxisome proliferator-activated receptor and ACSL1/4 and activation of GPX4 pathways. Importantly, FAM60A knockdown sensitized PDAC cells to gemcitabine treatment. A new understanding of FAM60A transcriptional regulation pattern in PDAC and its dual function in ferroptosis reliever and chemotherapy resistance is provided by our study. Targeting FAM60A may therefore offer a promising therapeutic approach for PDAC by simultaneously addressing 2 major features of the disease (high RAS mutation rate and tumor microenvironment nutrient deficiency) and preventing tumor cell metabolic adaptation.
铁死亡是一种非凋亡形式的细胞死亡，是包括癌症在内的多种疾病新出现的潜在治疗靶点。然而，铁死亡在胰腺癌中的作用仍知之甚少。胰腺导管腺癌（PDAC）的特点是预后差和化疗耐药，这归因于其高 Kirsten 大鼠肉瘤病毒癌基因同源物突变率以及由致密基质导致的严重营养缺乏。多项研究已将大鼠肉瘤（RAS）突变与铁死亡联系起来，表明诱导铁死亡可能是对抗携带致癌 RAS 的肿瘤的有效策略。在本研究中，我们调查了序列相似性家族 60 成员 A（FAM60A）的作用，该蛋白与预后不良密切相关且在 Kras;Trp53;Pdx1-Cre 小鼠的 PDAC 和肿瘤组织中高表达，其在体外和体内调节铁死亡、肿瘤生长及吉西他滨敏感性。我们的结果表明，FAM60A 调节 3 种关键代谢酶，即 ACSL1/4 和 GPX4，以保护 PDAC 细胞免于铁死亡。此外，我们发现 YY1 通过促进其转录在转录水平调节 FAM60A 的表达，并且在营养剥夺情况下，Hippo-YY1 通路在低氨基酸环境中受到限制，导致过氧化物酶体增殖物激活受体和 ACSL1/4 的下游抑制以及 GPX4 通路的激活。重要的是，FAM60A 基因敲低使 PDAC 细胞对吉西他滨治疗敏感。我们的研究提供了对 PDAC 中 FAM60A 转录调控模式及其在铁死亡缓解和化疗耐药中的双重功能的新认识。因此，靶向 FAM60A 可能通过同时解决该疾病的两个主要特征（高 RAS 突变率和肿瘤微环境营养缺乏）并防止肿瘤细胞代谢适应，为 PDAC 提供一种有前景的治疗方法。
Zotero 插件
