KCNN4-mediated Ca2+/MET/AKT axis is promising for targeted therapy of pancreatic ductal adenocarcinoma.

Abstract

As a member of the potassium calcium-activated channel subfamily, increasing evidence suggests that KCNN4 was associated with malignancies. However, the roles and regulatory mechanisms of KCNN4 in PDAC have been little explored. In this work, we demonstrated that the level of KCNN4 in PDAC was abnormally elevated, and the overexpression of KCNN4 was induced by transcription factor AP-1. KCNN4 was closely correlated with unfavorable clinicopathologic characteristics and poor survival. Functionally, we found that overexpression of KCNN4 promoted PDAC cell proliferation, migration and invasion. Conversely, the knockdown of KCNN4 attenuated the growth and motility of PDAC cells. In addition to these, knockdown of KCNN4 promoted PDAC cell apoptosis and led to cell cycle arrest in the S phase. In mechanistic investigations, RNA-sequence revealed that the MET-mediated AKT axis was essential for KCNN4, encouraging PDAC cell proliferation and migration. Collectively, these findings reveal a function of KCNN4 in PDAC and suggest it's an attractive therapeutic target and tumor marker. Our studies underscore a better understanding of the biological mechanism of KCNN4 in PDAC and suggest novel strategies for cancer therapy.

• Authors: Xiao Mo, Cheng-Fei Zhang, Ping Xu, Min Ding, Zhi-Jie Ma, Qi Sun, Yu Liu, Hong-Kai Bi, Xin Guo, Alaa Abdelatty, Chao Hu, Hao-Jun Xu, Guo-Ren Zhou, Yu-Liang Jia, Hong-Ping Xia
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 43 Issue 3 Pg. 735-746 (Mar 2022) ISSN: 1745-7254 [Electronic] United States
• PMID: 34183755 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to CPS and SIMM.

Chemical References

• Biomarkers, Tumor
• Intermediate-Conductance Calcium-Activated Potassium Channels
• Transcription Factor AP-1
• Proto-Oncogene Proteins c-met
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis (physiology)
• Biomarkers, Tumor
• Carcinoma, Pancreatic Ductal (pathology)
• Cell Line, Tumor
• Cell Movement (physiology)
• Cell Proliferation (physiology)
• Gene Knockdown Techniques
• Humans
• Intermediate-Conductance Calcium-Activated Potassium Channels (metabolism)
• Mice
• Pancreatic Neoplasms (pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-met (metabolism)
• Transcription Factor AP-1 (metabolism)
• Xenograft Model Antitumor Assays
• Pancreatic Neoplasms