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Peer-reviewedCC BY 4.0Cells

Disruption of p-AKT/ERβ-Mediated Midkine Signaling Promotes the Antimetastatic Effects of Timosaponin AIII in Nasopharyngeal Carcinoma Cells

  • Chu-Che Lee1,2
  • Yong-Syuan Chen3
  • Shun-Fa Yang1,3
  • Chu-Liang Lin1
  • Yi-Hsien Hsieh1,3
  • Chun-Yi Chuang4,5
5 affiliations
  1. 1Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
  2. 2Department of Medicine Research, Buddhist Dalin Tzu Chi Hospital, Chiayi 62247, Taiwan
  3. 3Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
  4. 4School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
  5. 5Department of Otolaryngology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
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Abstract

Background: Nasopharyngeal carcinoma (NPC) is a highly metastatic epithelial malignancy with limited therapeutic options for advanced disease. Timosaponin AIII (TSAIII), a natural steroidal saponin, exhibits antitumor activity; however, its effects on NPC progression and the molecular mechanisms remain unclear. Method: Cell viability, proliferation, apoptosis, migration, and invasion were evaluated using cell growth, colony formation, Annexin V/PI, and Transwell assays. Human chemokine array and The Cancer Genome Atlas (TCGA) analyses identified midkine (MDK) as a potential molecular target of TSAIII and its clinical relevance in NPC. Western blotting, qRT-PCR, immunofluorescence, and chromatin immunoprecipitation (ChIP) assays were used to investigate the underlying signaling mechanisms. Antimetastatic activity was further evaluated in C.B17-SCID mice. Results: TSAIII suppressed NPC cell migration and invasion with minimal cytotoxicity, accompanied by reduced the expression of p-AKT (Ser473), estrogen receptor β(ERβ) nuclear localization, and MDK expression. Wortmannin enhanced these effects, while TSAIII attenuated latent membrane protein 1 (LMP1)-induced signaling. In vivo, TSAIII significantly reduced lung metastasis without apparent toxicity. Conclusions: TSAIII suppresses NPC metastasis by targeting the LMP1/p-AKT/ERβ/MDK signaling axis, supporting its potential as an antimetastatic therapeutic candidate for NPC.

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Cite

BibTeXRIS
BibTeX
@article{lee2026disruption,
  title = {{Disruption of p-AKT/ERβ-Mediated Midkine Signaling Promotes the Antimetastatic Effects of Timosaponin AIII in Nasopharyngeal Carcinoma Cells}},
  author = {Chu-Che Lee and Yong-Syuan Chen and Shun-Fa Yang and Chu-Liang Lin and Yi-Hsien Hsieh and Chun-Yi Chuang},
  journal = {Cells},
  year = {2026},
  month = oct,
  doi = {10.3390/cells15211989},
  url = {https://www.mdpi.com/2073-4409/15/21/1989},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Disruption of p-AKT/ERβ-Mediated Midkine Signaling Promotes the Antimetastatic Effects of Timosaponin AIII in Nasopharyngeal Carcinoma Cells
AU  - Chu-Che Lee
AU  - Yong-Syuan Chen
AU  - Shun-Fa Yang
AU  - Chu-Liang Lin
AU  - Yi-Hsien Hsieh
AU  - Chun-Yi Chuang
PY  - 2026
DA  - 2026/10/31
JO  - Cells
DO  - 10.3390/cells15211989
UR  - https://www.mdpi.com/2073-4409/15/21/1989
AB  - Background: Nasopharyngeal carcinoma (NPC) is a highly metastatic epithelial malignancy with limited therapeutic options for advanced disease. Timosaponin AIII (TSAIII), a natural steroidal saponin, exhibits antitumor activity; however, its effects on NPC progression and the molecular mechanisms remain unclear. Method: Cell viability, proliferation, apoptosis, migration, and invasion were evaluated using cell growth, colony formation, Annexin V/PI, and Transwell assays. Human chemokine array and The Cancer Genome Atlas (TCGA) analyses identified midkine (MDK) as a potential molecular target of TSAIII and its clinical relevance in NPC. Western blotting, qRT-PCR, immunofluorescence, and chromatin immunoprecipitation (ChIP) assays were used to investigate the underlying signaling mechanisms. Antimetastatic activity was further evaluated in C.B17-SCID mice. Results: TSAIII suppressed NPC cell migration and invasion with minimal cytotoxicity, accompanied by reduced the expression of p-AKT (Ser473), estrogen receptor β(ERβ) nuclear localization, and MDK expression. Wortmannin enhanced these effects, while TSAIII attenuated latent membrane protein 1 (LMP1)-induced signaling. In vivo, TSAIII significantly reduced lung metastasis without apparent toxicity. Conclusions: TSAIII suppresses NPC metastasis by targeting the LMP1/p-AKT/ERβ/MDK signaling axis, supporting its potential as an antimetastatic therapeutic candidate for NPC.
SN  - 2073-4409
ER  -