2. Academic Validation
  3. Targeting the SPC25/RIOK1/MYH9 Axis to Overcome Tumor Stemness and Platinum Resistance in Epithelial Ovarian Cancer

Targeting the SPC25/RIOK1/MYH9 Axis to Overcome Tumor Stemness and Platinum Resistance in Epithelial Ovarian Cancer

  • Adv Sci (Weinh). 2024 Dec;11(47):e2406688. doi: 10.1002/advs.202406688.
Xingyu Jiang 1,  Muwen Yang 2,  Weijing Zhang 3,  Dongni Shi 1,  Yue Li 1,  Lixin He 1,  Shumei Huang 4,  Boyu Chen 1,  Xuwei Chen 1,  Lingzhi Kong 5,  Yibing Pan 1,  Pinwei Deng 1,  Rui Wang 1,  Ying Ouyang 1,  Xiangfu Chen 1,  Jun Li 4,  Zheng Li 6,  Hequn Zou 7,  Yanna Zhang 8,  Libing Song 1
Affiliations

Affiliations

  • 1 Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China.
  • 2 Department of Radiation Oncology, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, 518036, China.
  • 3 Department of Radiology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China.
  • 4 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China.
  • 5 Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China.
  • 6 Department of Gynecologic Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital), Kunming, Yunnan, 650118, China.
  • 7 School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China.
  • 8 Department of Gynecology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China.
PMID: 39488790 DOI: 10.1002/advs.202406688
Abstract

In epithelial ovarian Cancer (EOC), platinum resistance, potentially mediated by Cancer Stem Cells (CSCs), often leads to relapse and treatment failure. Here, the role of spindle pole body component 25 (SPC25) as a key determinant promoting stemness and platinum resistance in EOC cells, with its expression being correlated with adverse clinical outcomes is delineated. Mechanistically, SPC25 acts as a scaffolding platform, orchestrating the assembly of an SPC25/RIOK1/MYH9 trimeric complex, triggering RIOK1-mediated phosphorylation of MYH9 at Ser1943. This prompts MYH9 to disengage from the Cytoskeleton, augmenting its nuclear accumulation, thus potentiating CTNNB1 transcription and subsequent activation of Wnt/β-catenin signaling. CBP1, a competitive inhibitory peptide, can disrupt the formation of the aforementioned trimeric complex, diminishing the activity of the SPC25/RIOK1/MYH9 axis-mediated Wnt/β-catenin signaling, and thus attenuate CSC phenotypes, thereby enhancing platinum efficacy in vitro, in vivo, and in patient-derived organoids. Therefore, targeting the SPC25/RIOK1/MYH9 axis, which mediates the maintenance of stemness and platinum resistance in EOC cells, may enhance platinum sensitivity and increase survival in patients with EOC.

Keywords

SPC25; cancer stem cell; cell‐penetrating peptide; epithelial ovarian cancer; phosphorylation; platinum resistance; protein‐protein interaction.

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