PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis.
PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis.
复制标题
DOI：
10.1038/s41419-023-05885-y
复制
发表时间：
2023-06-24
影响因子：
9
通讯作者：
Lu, Xincheng
中科院分区：
文献类型：
--
作者：
Pan, Rulu;Dai, Juji;Liang, Weicheng;Wang, Hongxiao;Ye, Lin;Ye, Siqi;Lin, Ziqi;Huang, Shishun;Xiong, Yan;Zhang, Li;Lu, Liting;Wang, Ouchen;Shen, Xian;Liao, Wanqin;Lu, Xincheng
磷酸二酯酶4D相互作用蛋白（PDE 4DIP）是一种与环核苷酸磷酸二酯酶相关的中心体/高尔基体蛋白。PDE 4DIP通常在人类癌症中突变，其在小鼠中的改变导致肠癌的易感性。然而，PDE 4DIP在人类癌症中的生物学功能仍然不清楚。在这里，我们首次报告了PDE 4DIP在结直肠癌（CRC）生长和适应性MEK抑制剂（MEKi）耐药性中的致癌作用。我们发现PDE 4DIP在结直肠癌组织中表达上调，并与结直肠癌患者的临床特征和不良预后相关。PDE 4DIP的敲低通过抑制核心RAS信号传导途径损害KRAS突变CRC细胞的生长。PDE 4DIP通过抑制RAS GTP酶激活蛋白（RasGAP）神经纤维蛋白（NF 1）的表达，在致癌RAS/ERK信号传导的完全激活中发挥重要作用。在机制上，PDE 4DIP促进PLCγ/PKCε向高尔基体的募集，导致PKCε的组成性激活，从而触发NF 1的降解。PDE 4DIP的上调通过重新激活RAS/ERK通路导致KRAS突变型CRC中的适应性MEKi抗性。我们的工作揭示了PDE 4DIP和NF 1/RAS信号转导之间的一种新的功能联系，并表明靶向PDE 4DIP是KRAS突变型CRC的一种有前途的治疗策略。
Phosphodiesterase 4D interacting protein (PDE4DIP) is a centrosome/Golgi protein associated with cyclic nucleotide phosphodiesterases. PDE4DIP is commonly mutated in human cancers, and its alteration in mice leads to a predisposition to intestinal cancer. However, the biological function of PDE4DIP in human cancer remains obscure. Here, we report for the first time the oncogenic role of PDE4DIP in colorectal cancer (CRC) growth and adaptive MEK inhibitor (MEKi) resistance. We show that the expression of PDE4DIP is upregulated in CRC tissues and associated with the clinical characteristics and poor prognosis of CRC patients. Knockdown of PDE4DIP impairs the growth of KRAS-mutant CRC cells by inhibiting the core RAS signaling pathway. PDE4DIP plays an essential role in the full activation of oncogenic RAS/ERK signaling by suppressing the expression of the RAS GTPase-activating protein (RasGAP) neurofibromin (NF1). Mechanistically, PDE4DIP promotes the recruitment of PLCγ/PKCε to the Golgi apparatus, leading to constitutive activation of PKCε, which triggers the degradation of NF1. Upregulation of PDE4DIP results in adaptive MEKi resistance in KRAS-mutant CRC by reactivating the RAS/ERK pathway. Our work reveals a novel functional link between PDE4DIP and NF1/RAS signal transduction and suggests that targeting PDE4DIP is a promising therapeutic strategy for KRAS-mutant CRC.
登录
查看更多内容
影响因子：
3.3
作者：
Peng H;Zhang J;Ya A;Ma W;Villa S;Sukenik S;Ge X
通讯作者：
Ge X
影响因子：
28.2
作者：
Fedele C;Ran H;Diskin B;Wei W;Jen J;Geer MJ;Araki K;Ozerdem U;Simeone DM;Miller G;Neel BG;Tang KH
通讯作者：
Tang KH
影响因子：
50.3
作者：
McGillicuddy LT;Fromm JA;Hollstein PE;Kubek S;Beroukhim R;De Raedt T;Johnson BW;Williams SM;Nghiemphu P;Liau LM;Cloughesy TF;Mischel PS;Parret A;Seiler J;Moldenhauer G;Scheffzek K;Stemmer-Rachamimov AO;Sawyers CL;Brennan C;Messiaen L;Mellinghoff IK;Cichowski K
通讯作者：
Cichowski K
影响因子：
2.7
作者：
Ding, Yubo;Yao, Jingwei;Wen, Meiling;Liu, Xiong;Huang, Jialu;Zhang, Minghui;Zhang, Yu;Lv, Yufan;Xie, Zhuoyi;Zuo, JianHong
通讯作者：
Zuo, JianHong
影响因子：
29
作者：
Auer PL;Nalls M;Meschia JF;Worrall BB;Longstreth WT Jr;Seshadri S;Kooperberg C;Burger KM;Carlson CS;Carty CL;Chen WM;Cupples LA;DeStefano AL;Fornage M;Hardy J;Hsu L;Jackson RD;Jarvik GP;Kim DS;Lakshminarayan K;Lange LA;Manichaikul A;Quinlan AR;Singleton AB;Thornton TA;Nickerson DA;Peters U;Rich SS;National Heart, Lung, and Blood Institute Exome Sequencing Project
通讯作者：
National Heart, Lung, and Blood Institute Exome Sequencing Project