纳米颗粒向化疗耐药卵巢癌揭示了治疗脆弱性的双轴,涉及胆固醇吸收和细胞再氧化平衡
Yinu Wang1, Andrea E Calvert2, Horacio Cardenas1
1Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
|January 24, 2024
概括
抗的卵巢癌细胞通过SR-B1.1积累胆固醇. 用HDL纳米颗粒阻止这种受体会诱导铁亡,使瘤对化疗重新敏感,并抑制生长.
科学领域:
- 在瘤学瘤学.
- 生物化学 生物化学
- 分子生物学分子生物学
背景情况:
- 基于的化疗是卵巢癌 (OC) 的首要治疗方法.
- 获得的抗性 (Pt-R) 仍然是OC治疗中的重大临床挑战.
- Pt-R OC 细胞表现出细胞内胆固醇水平的增加,这种增加是由 HDL 受体,食肉受体 B-1 型 (SR-B1) 介导的.
研究的目的:
- 为了研究胆固醇代谢在卵巢癌中抗性的作用.
- 探索SR-B1作为克服白金耐药性的治疗目标.
- 阐明链接胆固醇,铁和敏感性的分子机制.
主要方法:
- 使用合成的缺乏胆固醇的HDL样纳米颗粒 (HDLNP) 来阻止SR-B1.1.
- 在Pt-R OC模型中评估胆固醇吸收,细胞活力和瘤生长抑制.
- 研究了SR-B1阻断对氧化应激,谷氨过氧化酶4 (GPx4) 和铁灭症诱导的影响.
- 检查了涉及EP300,H3K27Ac,SREBF2和SR-B1表达的下游分子通路.
主要成果:
- 用HDLNP阻塞SR-B1显著降低了Pt-ROC细胞中的胆固醇吸收.
- 这种干预导致细胞活力下降和瘤生长抑制.
- 降低胆固醇积累诱导脂质氧化应激和ferroptosis通过GPx4耗尽.
- 由于GPx4的耗尽,SR-B1的表达减少,并对化疗重新敏感.
- 从机制上讲,GPx4的淘汰抑制了EP300,导致SREBF2促进体上的H3K27Ac减少,从而降低了SREBF2的下调,随后SR-B1.
结论:
- 准SR-B1调节胆固醇吸收是一种可行的策略,以克服卵巢癌中的抗性.
- SR-B1-胆固醇-GPx4-SREBF2轴代表了Pt-R OC中的一个关键漏洞.
- 该轴的抑制会诱导铁亡并恢复对化疗的敏感性,从而提供了一种新的治疗方法.
更多相关视频
09:40Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
2.7K
07:54Surface-enhanced Resonance Raman Scattering Nanoprobe Ratiometry for Detecting Microscopic Ovarian Cancer via Folate Receptor Targeting
Published on: March 25, 2019
8.2K
相关概念视频
02:57Targeted Cancer Therapies
7.6K
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...
7.6K
02:49Cancer Therapies
7.7K
Cancer therapies are various modes of treatment, such as surgery, radiation therapy, and chemotherapy that are administered to cancer patients.
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
7.7K
02:56Treatment Resistant Cancers
3.3K
Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.3K