KCNJ15 deficiency promotes drug resistance via affecting the function of lysosomes

Xinbo Qiao; Yixiao Zhang; Zhan Zhang; Nan Niu; Haonan Li; Lisha Sun; Qingtian Ma; Jiawen Bu; Jinchi Liu; Guanglei Chen; Jinqi Xue; Yongliang Yang; Caigang Liu

doi:10.1016/j.ajps.2023.100814

KCNJ15 deficiency promotes drug resistance via affecting the function of lysosomes

Asian J Pharm Sci. 2023 May;18(3):100814. doi: 10.1016/j.ajps.2023.100814. Epub 2023 May 12.

Authors

Xinbo Qiao^{1

2

3}, Yixiao Zhang^{1

2

3}, Zhan Zhang^{1

2

3}, Nan Niu^{1

2}, Haonan Li⁴, Lisha Sun^{1

2

3}, Qingtian Ma^{1

2

3}, Jiawen Bu^{1

2

3}, Jinchi Liu^{1

2

3}, Guanglei Chen^{1

2}, Jinqi Xue^{1

2}, Yongliang Yang^{1

4}, Caigang Liu^{1

2

3}

Affiliations

¹ Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110000, China.
² Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, Shenyang 110000, China.
³ Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shenyang 110000, China.
⁴ School of Bioengineering, Dalian University of Technology, Dalian 116000, China.

Abstract

The altered lysosomal function can induce drug redistribution which leads to drug resistance and poor prognosis for cancer patients. V-ATPase, an ATP-driven proton pump positioned at lysosomal surfaces, is responsible for maintaining the stability of lysosome. Herein, we reported that the potassium voltage-gated channel subfamily J member 15 (KCNJ15) protein, which may bind to V-ATPase, can regulate the function of lysosome. The deficiency of KCNJ15 protein in breast cancer cells led to drug aggregation as well as reduction of drug efficacy. The application of the V-ATPase inhibitor could inhibit the binding between KCNJ15 and V-ATPase, contributing to the amelioration of drug resistance. Clinical data analysis revealed that KCNJ15 deficiency was associated with higher histological grading, advanced stages, more metastases of lymph nodes, and shorter disease free survival of patients with breast cancer. KCNJ15 expression level is positively correlated with a high response rate after receiving neoadjuvant chemotherapy. Moreover, we revealed that the small molecule drug CMA/BAF can reverse drug resistance by disrupting the interaction between KCNJ15 and lysosomes. In conclusion, KCNJ15 could be identified as an underlying indicator for drug resistance and survival of breast cancer, which might guide the choice of therapeutic strategies.

Keywords: Breast cancer; Cancer progression; Drug resistance; KCNJ15; Lysosome.