ABCA2,即ATP结合盒转运蛋白A2,是ATP结合盒转运蛋白家族的成员之一,主要表达于神经组织和巨噬细胞中。它是一种内溶酶体膜蛋白,参与多种生理功能,包括维持固醇、神经酰胺和胆固醇的内稳态。ABCA2在脑组织中高度表达,其敲除小鼠表现出神经缺陷,与异常的髓鞘形成有关[1,3]。此外,ABCA2的表达与对某些具有甾体骨架的抗肿瘤药物的耐药性有关,其基因表达受到甾醇的调控[1]。在巨噬细胞中,ABCA2受甾醇的影响,并在调节胆固醇隔离方面发挥作用,这在心血管疾病中可能具有重要意义[1]。ABCA2还在介导细胞内室中的神经酰胺运动方面起着关键作用,这些神经酰胺在胆固醇转运的各个方面都起着作用[1]。由于ABCA2的功能与膜构建块有关,因此有报道称它与人类病理学有关,包括胆固醇血症、心血管疾病、阿尔茨海默病和癌症[1,2,4,6]。研究表明,ABCA2在调节肿瘤细胞中脂质转运和药物耐药性方面起着重要作用,包括肿瘤干细胞[2]。ABCA2的过表达与癌症细胞对多种化合物的耐药性有关,包括雌二醇、米托蒽醌和自由基启动剂[4]。ABCA2在调节低密度脂蛋白(LDL)衍生胆固醇和甾醇相关化合物的转运和代谢中发挥着重要作用[4,6]。此外,ABCA2的表达与阿尔茨海默病(AD)有关,其基因中的一个单核苷酸多态性(SNP)被发现与早期发病的AD有关[4,6,8]。ABCA2突变导致小鼠大脑中神经酰胺代谢异常,包括神经节苷脂的显著积累和鞘磷脂(SM)的减少[7]。ABCA2的表达在成体啮齿动物脑中的神经祖细胞和神经元亚群中持续存在,这些神经元是AD病变的靶点[9]。在口腔鳞状细胞癌细胞中,ABCA2和其单核苷酸多态性(SNPs)在调节多药耐药性方面起着重要作用,这可能有助于克服多药耐药性并提高化疗药物的有效性[5]。ABCA2基因的多态性还与卡培他滨诱导的粒细胞减少症有关,这表明ABCA2在卡培他滨的药代动力学和毒性方面发挥作用[8]。综上所述,ABCA2在多种生理和病理过程中发挥着重要作用,包括神经酰胺代谢、胆固醇转运和药物耐药性。ABCA2的异常表达与多种疾病的发生和发展有关,包括阿尔茨海默病、心血管疾病和癌症。因此,ABCA2可能是一个有潜力的治疗靶点,为这些疾病的治疗提供了新的思路和策略。
参考文献:
1. Davis, Warren, Tew, Kenneth D. 2017. ATP-binding cassette transporter-2 (ABCA2) as a therapeutic target. In Biochemical pharmacology, 151, 188-200. doi:10.1016/j.bcp.2017.11.018. https://pubmed.ncbi.nlm.nih.gov/29223352/
2. Mack, Jody T, Brown, Carol B, Tew, Kenneth D. . ABCA2 as a therapeutic target in cancer and nervous system disorders. In Expert opinion on therapeutic targets, 12, 491-504. doi:10.1517/14728222.12.4.491. https://pubmed.ncbi.nlm.nih.gov/18348684/
3. Schmitz, G, Kaminski, W E. . ABCA2: a candidate regulator of neural transmembrane lipid transport. In Cellular and molecular life sciences : CMLS, 59, 1285-95. doi:. https://pubmed.ncbi.nlm.nih.gov/12363033/
4. Mack, Jody T, Townsend, Danyelle M, Beljanski, Vladimir, Tew, Kenneth D. . The ABCA2 transporter: intracellular roles in trafficking and metabolism of LDL-derived cholesterol and sterol-related compounds. In Current drug metabolism, 8, 47-57. doi:. https://pubmed.ncbi.nlm.nih.gov/17266523/
5. Kim, Mi Seong, Yang, Sei Hoon, Kim, Min Seuk. 2023. Role of ABCA2 and its single nucleotide polymorphisms (4873T>A and 4879G>C) in the regulation of multi-drug resistance in oral squamous carcinoma cells. In Biochemical and biophysical research communications, 666, 1-9. doi:10.1016/j.bbrc.2023.05.021. https://pubmed.ncbi.nlm.nih.gov/37167718/
6. Mack, J T, Beljanski, V, Tew, K D, Townsend, D M. 2006. The ATP-binding cassette transporter ABCA2 as a mediator of intracellular trafficking. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 60, 587-92. doi:. https://pubmed.ncbi.nlm.nih.gov/17029687/
7. Sakai, Hiromichi, Tanaka, Yukiko, Tanaka, Makoto, Kita, Toru, Inagaki, Nobuya. 2007. ABCA2 deficiency results in abnormal sphingolipid metabolism in mouse brain. In The Journal of biological chemistry, 282, 19692-9. doi:. https://pubmed.ncbi.nlm.nih.gov/17488728/
8. Shibata, Yukitaka, Matsumoto, Natsumi, Murase, Remi, Shimada, Ken, Fujita, Ken-Ichi. 2023. A polymorphism in ABCA2 is associated with neutropenia induced by capecitabine in Japanese patients with colorectal cancer. In Cancer chemotherapy and pharmacology, 92, 465-474. doi:10.1007/s00280-023-04584-x. https://pubmed.ncbi.nlm.nih.gov/37653272/
9. Broccardo, Cyril, Nieoullon, Vincent, Amin, Rada, Chazal, Genèvieve, Chimini, Giovanna. 2006. ABCA2 is a marker of neural progenitors and neuronal subsets in the adult rodent brain. In Journal of neurochemistry, 97, 345-55. doi:. https://pubmed.ncbi.nlm.nih.gov/16539677/