PI3K途径是食道中NRF2激活的下游效应因子
Boopathi Subramaniyan1, Yahui Li1, Zhaohui Xiong2
1Surgical Research Lab, Department of Surgery, Cooper University Health Care, Camden, NJ, 08103, USA.
Translational oncology
|December 4, 2025
概括
核因子红色素2相关因子2 (NRF2) 的突变在食道状细胞癌中激活癌症途径. 向NRF2和PI3K通路显示出对治疗NRF2突变ESCC的希望.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 核因子红色素2相关因子2 (NFE2L2或NRF2) 的突变在食道状细胞癌 (ESCC) 中很常见,导致NRF2激活.
- 激活的NRF2促进瘤进展和治疗耐药性,但特定的下游激酶在很大程度上仍未确定.
研究的目的:
- 在ESCC中识别响应NRF2激活的特定激酶.
- 为了研究酸丁3-激酶 (PI3K) 途径在NRF2-驱动ESCC中的作用.
- 评估NRF2和PI3K通路的共同向的治疗潜力.
主要方法:
- 在NRF2-突变与NRF2-无ESCC细胞中的蛋白质酸化和激酶活性概况.
- 在体内研究中,使用ESCC的基因工程小鼠模型.
- 对人类ESCC组织的分析,以将NRF2激活与途径标记者相关联.
主要成果:
- 确定PI3K途径是NRF2激活的关键下游效应因子.
- 由于NRF2缺乏,ESCC细胞对EGFR,PIK3CA和AKT抑制剂产生了敏感性.
- 与NRF2和PI3K抑制剂的同时治疗在体外和体内协同抑制了瘤生长.
- 在人类ESCC组织中,NRF2激活与PI3K通路激活相关.
结论:
- PI3K途径是食道癌中NRF2激活的关键下游标.
- 联合抑制NRF2和PI3K通路代表了对NRF2突变ESCC的有前途的治疗策略.
相关概念视频
Interactions Between Signaling Pathways
7.2K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
7.2K
PI3K/mTOR/AKT Signaling Pathway
5.3K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
5.3K
MAPK Signaling Cascades
7.8K
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
7.8K
NF-κB-dependent Signaling Pathway
9.7K
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
NF-κB-dependent Signaling Mechanism
The...
9.7K
The JAK-STAT Signaling Pathway
11.8K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
11.8K
Regulation of the Unfolded Protein Response
2.9K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.9K
