Inhibition of HOXC11 by artesunate induces ferroptosis and suppresses ovarian cancer progression through transcriptional regulation of the PROM2/PI3K/AKT pathway

  • World J Surg Oncol. 2024 Oct 8;22(1):268. doi: 10.1186/s12957-024-03544-w.
Jun Li  #  1  2 ,  Lu Feng  #  2 ,  Yijun Yuan  2 ,  Tianwen He  2 ,  Xinru Zou  2 ,  Bin Su  2 ,  Kang Liu  3 ,  Xiaojun Yang  4
Affiliations
  • 1. Department of Obstetrics and Gynecology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, PR China.
  • 2. Department of Obstetrics and Gynecology, Nanchong Central Hospital, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, Sichuan, PR China.
  • 3. Institute of Tissue Engineering and Stem Cell, Nanchong Central Hospital, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, Sichuan, PR China.
  • 4. Department of Obstetrics and Gynecology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, PR China. [email protected].
  • # Contributed equally.
PMID: 39380001 DOI: 10.1186/s12957-024-03544-w
Abstract

Background: Ferroptosis, a non-apoptotic form of regulated cell death, plays a critical role in the suppression of various tumor types, including ovarian Cancer. Artesunate (ART), a derivative of artemisinin, exhibits extensive antitumor effects and is associated with Ferroptosis. This study aimed to investigate the mechanisms through which ART induces Ferroptosis to inhibit ovarian Cancer.

Methods: RNA Sequencing was conducted to identify differentially expressed genes associated with ART-induced Ferroptosis. Dual-luciferase reporter assays and electrophoretic mobility shift assays were performed to confirm the interaction between Homeobox C11 (HOXC11) and the Prominin 2 (PROM2) promoter. Cell Counting Kit-8 (CCK-8) assays, flow cytometry, and wound healing assays were used to analyze the antitumor effects of ART. Western blot, biochemical assays and transmission electron microscope were utilized to further characterize ART-induced Ferroptosis. In vivo, the effects of ART on Ferroptosis were examined using a xenograft mouse model.

Results: RNA Sequencing analysis revealed that the HOXC11, PROM2 and Phosphatidylinositol 3-Kinase/ Protein Kinase B (PI3K/Akt) pathways were downregulated by ART. HOXC11 was found to regulate PROM2 expression by binding to its promoter directly. HOXC11 overexpression reversed ART-induced effects on ovarian Cancer cell proliferation, migration, Apoptosis and Ferroptosis by activating the PROM2/PI3K/Akt signaling axis. Conversely, silencing PROM2 in HOXC11-overexpressing cells restored ART-induced Ferroptosis and its associated antitumor effects by inhibiting the PI3K/Akt pathway. Consistently, in vivo studies using a xenograft mouse model confirmed that ART-induced tumor inhibition was mediated by Ferroptosis through the suppression of the HOXC11/PROM2/PI3K/Akt pathway.

Conclusion: This study identifies the HOXC11/PROM2/PI3K/Akt axis as a novel regulatory mechanism underlying ART-induced Ferroptosis in ovarian Cancer. Targeting the HOXC11/PROM2 axis may represent a promising therapeutic strategy for enhancing Ferroptosis, offering new insights for the treatment of ovarian Cancer.

Keywords
Artesunate; Ferroptosis; HOXC11; Ovarian cancer; PI3K/AKT signaling; PROM2.
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