IKBKE通过RRM2-AKT通路调节细胞癌的进展和苏尼替尼抗性
Shiwei Liu1,2,3, Junhong Li1,2,3, Junyu Zhang1,2,3
1Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
International journal of biological sciences
|December 12, 2024
概括
核因子卡帕B激酶亚单元epsilon (IKBKE) 的抑制剂促进细胞癌 (RCC) 的进展和抗苏尼替尼的抵抗性. 向IKBKE可能会克服耐药性并提高RCC治疗中sunitinib的疗效.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 像苏尼蒂尼布这样的氨酸激酶抑制剂 (TKI) 是晚期细胞癌 (RCC) 治疗的关键.
- 对苏尼提尼布的获得性耐药性是RCC中的一个重要的临床挑战.
- 核因子卡帕B激酶亚单元素 (IKBKE) 抑制剂越来越多地与癌症进展和耐药性有关.
研究的目的:
- 调查IKBKE在RCC进展和逊尼提尼布耐药性的作用.
- 探索IKBKE介导药物耐药性的潜在分子机制.
- 评估向IKBKE在RCC中的治疗潜力.
主要方法:
- 在RCC组织和抗苏尼提尼布细胞系中分析IKBKE表达.
- 沉默IKBKE以评估其对RCC细胞增殖,细胞循环和逊尼提尼布敏感性的影响.
- 调查IKBKE,核酸减少酶M2 (RRM2) 和AKT信号通路之间的相互作用.
- 评估IKBKE抑制剂 (CYT387) 在恢复逊尼提尼布敏感性的疗效.
主要成果:
- 在RCC组织和抗苏尼提尼布细胞中,IKBKE被上调,与晚期和不良预后相关.
- 通过降低RRM2的调控,IKBKE静音抑制了RCC的进展,诱导了G2/M细胞周期的停止,并增强了对sunitinib的敏感性.
- IKBKE直接与RRM2相互作用并酸化RRM2,激活AKT通路,从而推动RCC的进展和苏尼替尼抗性.
- 通过降低RRM2表达的调节,IKBKE抑制剂CYT387恢复了苏尼替尼的敏感性.
结论:
- 抑制IKBKE可以抑制RCC的进展,并通过RRM2-AKT通路增强sunitinib的敏感性.
- 在RCC中,IKBKE代表了一个潜在的治疗目标,用于克服RCC中sunitinib耐药性.
- 针对IKBKE可以提供一种新的策略,以改善晚期RCC患者的治疗结果.
相关概念视频
03:03mTOR Signaling and Cancer Progression
3.7K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.7K
01:22PI3K/mTOR/AKT Signaling Pathway
3.4K
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...
3.4K
02:34Inhibition of Cdk Activity
4.7K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.7K
01:20The Retinoblastoma Gene
4.1K
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
4.1K
02:38Mitogens and the Cell Cycle
6.4K
Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.4K
02:57Targeted Cancer Therapies
7.5K
The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
There are several types of targeted therapies against...
7.5K