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

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 abnor...

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Published inActa pharmacologica Sinica Vol. 43; no. 3; pp. 735 - 746
Main Authors Mo, Xiao, Zhang, Cheng-fei, Xu, Ping, Ding, Min, Ma, Zhi-jie, Sun, Qi, Liu, Yu, Bi, Hong-kai, Guo, Xin, Abdelatty, Alaa, Hu, Chao, Xu, Hao-jun, Zhou, Guo-ren, Jia, Yu-liang, Xia, Hong-ping
Format Journal Article
LanguageEnglish
Published Singapore Springer Singapore 01.03.2022
Nature Publishing Group
Subjects
Activator protein 1
Adenocarcinoma
AKT protein
Apoptosis
Biomedical and Life Sciences
Biomedicine
Cell cycle
Cell growth
Cell migration
Cell proliferation
Immunology
Internal Medicine
Medical Microbiology
Nucleotide sequence
Pancreatic cancer
Pharmacology/Toxicology
Potassium channels (calcium-gated)
S phase
Therapeutic targets
Transcription factors
Tumor markers
Tumors
Vaccine
AKT
proliferation
KCNN4
MET
pancreatic ductal adenocarcinoma
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Summary: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.
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ISSN:1671-4083
1745-7254
DOI:10.1038/s41401-021-00688-3