The Interaction of Calcium-Sensing Receptor with KIF11 Enhances Cisplatin Resistance in Lung Adenocarcinoma via BRCA1/cyclin B1 pathway

  • Int J Biol Sci. 2024 Jul 15;20(10):3892-3910. doi: 10.7150/ijbs.92046.
Fuhao Wang  1  2 ,  Xing Fu  1 ,  Ming Chang  1 ,  Tianzi Wei  1 ,  Risheng Lin  1 ,  Haibo Tong  3 ,  Xiao Zhang  1 ,  Runzhu Yuan  1  2 ,  Zhiqing Zhou  1 ,  Xin Huang  1 ,  Wei Zhang  4 ,  Wenmei Su  5 ,  Yi Lu  1  6 ,  Zhen Liang  2 ,  Jian Zhang  1  6
Affiliations
  • 1. School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
  • 2. The First Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
  • 3. Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, 999078, China.
  • 4. School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China.
  • 5. Department of Pulmonary Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
  • 6. Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
PMID: 39113697 DOI: 10.7150/ijbs.92046
Abstract

Cisplatin (DDP) is commonly used in the treatment of non-small cell lung Cancer (NSCLC), including lung adenocarcinoma (LUAD), and the primary cause for its clinical inefficacy is chemoresistance. Here, we aimed to investigate a novel mechanism of chemoresistance in LUAD cells, focusing on the calcium-sensing receptor (CaSR). In this study, high CaSR expression was detected in DDP-resistant LUAD cells, and elevated CaSR expression is strongly correlated with poor prognosis in LUAD patients receiving chemotherapy. LUAD cells with high CaSR expression exhibited decreased sensitivity to cisplatin, and the growth of DDP-resistant LUAD cells was inhibited by cisplatin treatment in combination with CaSR suppression, accompanied by changes in BRCA1 and cyclin B1 protein expression both in vitro and in vivo. Additionally, an interaction between CaSR and KIF11 was identified. Importantly, suppressing KIF11 resulted in decreased protein levels of BRCA1 and cyclin B1, enhancing the sensitivity of DDP-resistant LUAD cells to cisplatin with no obvious decrease in CaSR. Here, our findings established the critical role of CaSR in promoting cisplatin resistance in LUAD cells by modulating cyclin B1 and BRCA1 and identified KIF11 as a mediator, highlighting the potential therapeutic value of targeting CaSR to overcome chemoresistance in LUAD.

Keywords
BRCA1; CaSR; KIF11.; chemoresistance; cyclin B1; lung adenocarcinoma.
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