通过新型小分子抑制刺之路 损害黑色素瘤细胞在缺氧下迁移和入侵
Alessandro Falsini1, Gaia Giuntini1, Mattia Mori2
1Cellular and Molecular Physiology Unit, Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
Pharmaceuticals (Basel, Switzerland)
|February 24, 2024
概括
抑制刺通路和碳酸无水酶XII可以减少黑色素瘤细胞的迁移和入侵,特别是在低氧条件下. 多位抑制剂C22在治疗黑色素瘤方面表现有前途,没有细胞毒性.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 黑色素瘤转移是癌症死亡的主要原因.
- 瘤微环境 (TME) 缺氧促进了攻击性的黑色素瘤表型.
- 碳酸 anhydrase (CA) 活性和 Hedgehog (Hh) 信号与黑色素瘤的进展有关.
研究的目的:
- 为了研究碳酸无水酶XII (CAXII),缺氧和黑色素瘤中的Hh通路之间的相互作用.
- 评估Hh通路抑制对CAXII表达和黑色素瘤细胞入侵的影响.
- 评估针对Hh通路的新型化合物的疗效.
主要方法:
- 黑色素瘤细胞系 (SK-MEL-28,A375) 用Hh通路抑制剂 (cyclopamine, glabrescione B,C22) 进行治疗.
- 在低氧条件下分析CAXII表达.
- 在Smoothened和GLI1.1的化学抑制后,进行了细胞迁移和入侵试验.
主要成果:
- Hh通路的抑制,加上CAXII的降低,显著损害了黑色素瘤细胞的迁移和入侵,特别是在低氧状态下.
- 多目标Hh抑制剂C22在没有可观察到的细胞毒性的情况下显示出有效性.
- 数据表明,在黑色素瘤中,CAXII,缺氧和Hh通路激活之间存在功能联系.
结论:
- 准Hh通路和CAXII代表了黑色素瘤的潜在治疗策略.
- Hh抑制剂C22是进一步研究黑色素瘤治疗的有希望的候选者.
- 了解CAXII,缺氧和Hh信号之间的关系可以改善黑色素瘤疾病的治疗.
相关概念视频
02:33Hedgehog Signaling Pathway
7.4K
The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to...
7.4K
01:24Regulation of Angiogenesis and Blood Supply
2.6K
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
2.6K
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
01:31The Intrinsic Apoptotic Pathway
6.5K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.5K