Abcc5, an ATP-Binding Cassette Subfamily C Member 5, is a key player among the ABC transporter proteins. It reduces intracellular drug concentration using an ATP-dependent mechanism to pump drugs out of cells, contributing to multidrug resistance (MDR) in cancer [1]. Additionally, it may be involved in other biological processes such as the regulation of GLP-1 secretion [3].

In a global Abcc5 knockout mouse model, Abcc5-/-mice showed decreased fat mass, increased plasma levels of GLP-1, enhanced insulin sensitivity, and increased activity, suggesting that Abcc5 protein expression levels are inversely related to fat mass and play a role in GLP-1 secretion regulation [3]. In cancer research, down-regulation of Abcc5 in sorafenib-resistant hepatocellular carcinoma cells significantly reduced their resistance to sorafenib, and inhibition of Abcc5 enhanced sorafenib's anti-cancer activity in vitro and in vivo [2]. In breast cancer, Abcc5 expression was associated with pemetrexed resistance in vitro and in vivo, and stable knockdown of Abcc5 in breast cancer cells reduced bone metastatic burden and osteolytic bone destruction in mice [5,6].

In conclusion, Abcc5 is mainly known for its role in drug efflux and MDR in cancer. The Abcc5 knockout mouse model has been instrumental in revealing its function in metabolism-related processes like fat mass regulation and GLP-1 secretion. In the cancer context, loss-of-function experiments have demonstrated its potential as a therapeutic target for various cancers, including hepatocellular carcinoma, breast cancer, and castration-resistant prostate cancer [1,2,4,5,6].

References:

1. Pan, Yinlong, Wu, Mengmeng, Cai, Huazhong. 2024. Role of ABCC5 in cancer drug resistance and its potential as a therapeutic target. In Frontiers in cell and developmental biology, 12, 1446418. doi:10.3389/fcell.2024.1446418. https://pubmed.ncbi.nlm.nih.gov/39563862/

2. Huang, Wenbin, Chen, Kunling, Lu, Yishi, Zhao, Liang, Pan, Mingxin. 2021. ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma. In Neoplasia (New York, N.Y.), 23, 1227-1239. doi:10.1016/j.neo.2021.11.002. https://pubmed.ncbi.nlm.nih.gov/34768109/

3. Cyranka, Malgorzata, Veprik, Anna, McKay, Eleanor J, Cox, Roger D, de Wet, Heidi. . Abcc5 Knockout Mice Have Lower Fat Mass and Increased Levels of Circulating GLP-1. In Obesity (Silver Spring, Md.), 27, 1292-1304. doi:10.1002/oby.22521. https://pubmed.ncbi.nlm.nih.gov/31338999/

4. Chen, Haojie, Luo, Jia, Chen, Shaojun, Ding, Jie, Yu, Yongjiang. 2022. Non-drug efflux function of ABCC5 promotes enzalutamide resistance in castration-resistant prostate cancer via upregulation of P65/AR-V7. In Cell death discovery, 8, 241. doi:10.1038/s41420-022-00951-4. https://pubmed.ncbi.nlm.nih.gov/35504877/

5. Chen, Jihui, Wang, Zhipeng, Gao, Shouhong, Lu, Yunshu, Liu, Yan. 2021. Human drug efflux transporter ABCC5 confers acquired resistance to pemetrexed in breast cancer. In Cancer cell international, 21, 136. doi:10.1186/s12935-021-01842-x. https://pubmed.ncbi.nlm.nih.gov/33632224/

6. Mourskaia, Anna A, Amir, Eitan, Dong, Zhifeng, Komarova, Svetlana V, Siegel, Peter M. 2012. ABCC5 supports osteoclast formation and promotes breast cancer metastasis to bone. In Breast cancer research : BCR, 14, R149. doi:10.1186/bcr3361. https://pubmed.ncbi.nlm.nih.gov/23174366/