Cab39, also known as calcium-binding protein 39, is involved in multiple biological processes and signaling pathways. It is crucial for the phosphorylation and activation of the thiazide-sensitive NCC in the distal convoluted tubule for sodium-potassium balance, and is also associated with the AMP-activated protein kinase (AMPK) signaling pathway, which plays a role in energy homeostasis and cell stress responses [4,5,7,8,9].

In bladder cancer, knockdown of Cab39 in cisplatin-resistant cells made them more sensitive to cisplatin, indicating that Cab39 promotes cisplatin resistance through the LKB1-AMPK-LC3 pathway, enhancing autophagy to maintain mitochondrial health and reduce ROS levels [1]. In nasopharyngeal carcinoma, over-expression of Cab39 promoted the proliferation of CNE-1 cells via up-regulating p-JNK [2]. In bladder cancer, shRNA-mediated Cab39 knockdown mitigated the oncogenic trajectory, reversing invasive and metastatic behaviors [3]. In the context of cerebral ischemia/reperfusion injury, miR-32-3p facilitated injury by inhibiting Cab39/AMPK [5]. In non-small cell lung cancer, MAPKAPK5-AS1 upregulated Cab39 expression to facilitate cell proliferation and migration by sequestering miR-515-5p [6]. In osteoblasts, miR-107 inhibition upregulated Cab39 and activated the AMPK-Nrf2 signaling to protect against dexamethasone-induced oxidative injury [7]. In a rat model of glucocorticoid-induced osteoporosis, up-regulation of lncRNA TRG-AS1 protected against osteoporosis by modulating the miR-802-mediated CAB39/AMPK/SIRT-1/NF-κB axis [8]. In lipopolysaccharide-induced acute lung injury, miR-31-5p exacerbated the injury via inactivating Cab39/AMPKα pathway [9]. In hypertensive rats, augmented WNK-Cab39-NKCC1 signaling increased the susceptibility to ischemic brain damage [10].

In conclusion, Cab39 is involved in multiple biological processes and disease conditions. Through gene-knockout or knockdown models, it has been revealed that Cab39 plays important roles in cancer development, drug resistance, and various injury-related diseases, mainly through its association with key signaling pathways such as AMPK. These findings provide potential therapeutic targets for treating related diseases.

References:

1. Gao, Dongyang, Wang, Runchang, Gong, Yuwen, Lu, Jianzhong, Wang, Zhiping. 2023. CAB39 promotes cisplatin resistance in bladder cancer via the LKB1-AMPK-LC3 pathway. In Free radical biology & medicine, 208, 587-601. doi:10.1016/j.freeradbiomed.2023.09.017. https://pubmed.ncbi.nlm.nih.gov/37726090/

2. Peng, Lifen, Yan, Hailan, Qi, Shuyi, Deng, Lifei. 2020. CAB39 Promotes the Proliferation of Nasopharyngeal Carcinoma CNE-1 Cells via Up-Regulating p-JNK. In Cancer management and research, 12, 11203-11209. doi:10.2147/CMAR.S252476. https://pubmed.ncbi.nlm.nih.gov/33177871/

3. Huang, Jianbiao, Deng, Huanhuan, Xiao, Shuaiyun, Chao, Haichao, Zeng, Tao. 2024. CAB39 modulates epithelial-mesenchymal transition through NF-κB signaling activation, enhancing invasion, and metastasis in bladder cancer. In Environmental toxicology, 39, 4791-4802. doi:10.1002/tox.24333. https://pubmed.ncbi.nlm.nih.gov/39171884/

4. Ferdaus, Mohammed Z, Koumangoye, Rainelli B, Welling, Paul A, Delpire, Eric. 2024. Kinase Scaffold Cab39 Is Necessary for Phospho-Activation of the Thiazide-Sensitive NCC. In Hypertension (Dallas, Tex. : 1979), 81, 801-810. doi:10.1161/HYPERTENSIONAHA.123.22464. https://pubmed.ncbi.nlm.nih.gov/38258567/

5. Tao, Hongmiao, Dong, Lihua, Shan, Xiaoyun, Li, Lin, Chen, Haohao. 2023. MicroRNA-32-3p facilitates cerebral ischemia/reperfusion injury through inhibiting Cab39/AMPK. In International immunopharmacology, 121, 110504. doi:10.1016/j.intimp.2023.110504. https://pubmed.ncbi.nlm.nih.gov/37379707/

6. Zhao, Yueming, Zhou, Danyang, Yuan, Yuan, Tan, Yan, Fang, Surong. 2023. MAPKAPK5-AS1/miR-515-5p/CAB39 Axis Contributes to Non-small Cell Lung Cancer Cell Proliferation and Migration. In Molecular biotechnology, 65, 1887-1897. doi:10.1007/s12033-023-00654-w. https://pubmed.ncbi.nlm.nih.gov/36867352/

7. Zhuang, Yu, Wang, Shouguo, Fei, Haodong, Ji, Feng, Sun, Peng. 2020. miR-107 inhibition upregulates CAB39 and activates AMPK-Nrf2 signaling to protect osteoblasts from dexamethasone-induced oxidative injury and cytotoxicity. In Aging, 12, 11754-11767. doi:10.18632/aging.103341. https://pubmed.ncbi.nlm.nih.gov/32527986/

8. Liu, Wen, Li, Guojuan, Li, Jing, Chen, Wei. 2022. Long noncoding RNA TRG-AS1 protects against glucocorticoid-induced osteoporosis in a rat model by regulating miR-802-mediated CAB39/AMPK/SIRT-1/NF-κB axis. In Human cell, 35, 1424-1439. doi:10.1007/s13577-022-00741-1. https://pubmed.ncbi.nlm.nih.gov/35794445/

9. Jiang, Wan-Li, Zhao, Kao-Chang, Yuan, Wen, Zhao, Bo, Xie, Song-Ping. 2020. MicroRNA-31-5p Exacerbates Lipopolysaccharide-Induced Acute Lung Injury via Inactivating Cab39/AMPKα Pathway. In Oxidative medicine and cellular longevity, 2020, 8822361. doi:10.1155/2020/8822361. https://pubmed.ncbi.nlm.nih.gov/33101593/

10. Bhuiyan, Mohammad Iqbal H, Song, Shanshan, Yuan, Hui, Subramanya, Arohan R, Sun, Dandan. 2016. WNK-Cab39-NKCC1 signaling increases the susceptibility to ischemic brain damage in hypertensive rats. In Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 37, 2780-2794. doi:10.1177/0271678X16675368. https://pubmed.ncbi.nlm.nih.gov/27798271/