ABCC4, also known as multi-drug resistance protein-4 (MRP4), is an ATP-binding cassette (ABC) transporter. It is involved in the regulation of endogenous and exogenous substrates, playing a crucial role in processes like cAMP-dependent second messenger signaling and extracellular transport [1]. It has been implicated in various physiological and pathological pathways, with its dysregulation associated with numerous disorders [3]. Genetic models, such as gene knockout mouse models, are valuable for studying its function.

In megakaryopoiesis, Abcc4-/-mice showed impaired proplatelet formation and polyploidization, indicating that ABCC4 is required for optimal platelet formation [2]. In the context of cardiovascular disease, inhibition of MRP4 (ABCC4) in adult rat ventricular myocytes increased intracellular cAMP levels, enhancing cardiomyocyte contractility, but prolonged inhibition promoted cardiac hypertrophy [4]. In prostate cancer, depletion of ABCC4 in cancer cells halted the release of prostaglandin E2 (PGE2), which improved the efficacy of PD-1 blockade by reducing CD8 + T cell dysfunction [5]. In glioblastoma, ABCC4 loss-of-function activated cGMP-PKG signalling, promoting malignancy, and aspirin hydrogels, by upregulating ABCC4, augmented the efficacy of standard-of-care therapies [6]. In pancreatic cancer, modulation of ABCC4 levels in cell lines dysregulated genes in the epithelial-mesenchymal transition (EMT) signature, and in Abcc4-null mice, cytarabine-induced hematological toxicity was enhanced, suggesting ABCC4 protects against cytarabine-mediated insults in leukemic and host myeloid cells [7,8].

In conclusion, ABCC4 is essential for multiple biological processes, including platelet formation, cAMP homeostasis, and cellular signalling regulation. Through gene knockout mouse models, its role in various disease areas such as cancer, cardiovascular diseases, and response to chemotherapy has been revealed. These findings highlight the importance of ABCC4 as a potential therapeutic target in multiple disease conditions.

References:

1. Nguyen, Jenny P, Kim, Yechan, Cao, Quynh, Hirota, Jeremy A. 2021. Interactions between ABCC4/MRP4 and ABCC7/CFTR in human airway epithelial cells in lung health and disease. In The international journal of biochemistry & cell biology, 133, 105936. doi:10.1016/j.biocel.2021.105936. https://pubmed.ncbi.nlm.nih.gov/33529712/

2. Ranjit, Sabina, Wang, Yao, Zhu, Jingwen, Naren, Anjaparavanda P, Schuetz, John D. 2023. ABCC4 impacts megakaryopoiesis and protects megakaryocytes against 6-mercaptopurine induced cytotoxicity. In Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 72, 101017. doi:10.1016/j.drup.2023.101017. https://pubmed.ncbi.nlm.nih.gov/37988981/

3. Yaneff, Agustín, Sahores, Ana, Gómez, Natalia, Shayo, Carina, Davio, Carlos. . MRP4/ABCC4 As a New Therapeutic Target: Meta-Analysis to Determine cAMP Binding Sites as a Tool for Drug Design. In Current medicinal chemistry, 26, 1270-1307. doi:10.2174/0929867325666171229133259. https://pubmed.ncbi.nlm.nih.gov/29284392/

4. Belleville-Rolland, Tiphaine, Sassi, Yassine, Decouture, Benoit, Gaussem, Pascale, Bachelot-Loza, Christilla. 2016. MRP4 (ABCC4) as a potential pharmacologic target for cardiovascular disease. In Pharmacological research, 107, 381-389. doi:10.1016/j.phrs.2016.04.002. https://pubmed.ncbi.nlm.nih.gov/27063943/

5. Li, Le, Chao, Zheng, Peng, Hao, Wang, Zhihua, Zeng, Xing. 2024. Tumor ABCC4-mediated release of PGE2 induces CD8+ T cell dysfunction and impairs PD-1 blockade in prostate cancer. In International journal of biological sciences, 20, 4424-4437. doi:10.7150/ijbs.99716. https://pubmed.ncbi.nlm.nih.gov/39247809/

6. Chiang, Jung-Ying, Wei, Sung-Tai, Chang, Huan-Jui, Wang, Chi-Chung, Hsieh, Chia-Hung. 2024. ABCC4 suppresses glioblastoma progression and recurrence by restraining cGMP-PKG signalling. In British journal of cancer, 130, 1324-1336. doi:10.1038/s41416-024-02581-2. https://pubmed.ncbi.nlm.nih.gov/38347095/

7. Gancedo, S N, Sahores, A, Gómez, N, Davio, C A, González, B. 2024. The xenobiotic transporter ABCC4/MRP4 promotes epithelial mesenchymal transition in pancreatic cancer. In Frontiers in pharmacology, 15, 1432851. doi:10.3389/fphar.2024.1432851. https://pubmed.ncbi.nlm.nih.gov/39114357/

8. Drenberg, C D, Hu, S, Li, L, Sparreboom, A, Baker, S D. 2016. ABCC4 Is a Determinant of Cytarabine-Induced Cytotoxicity and Myelosuppression. In Clinical and translational science, 9, 51-9. doi:10.1111/cts.12366. https://pubmed.ncbi.nlm.nih.gov/26842729/