2. Academic Validation
  3. Nuclear export of transmembrane protein PROM2 is specially regulated by CRM1 and affects the sensitivity of ferroptosis in gastric cancer

Nuclear export of transmembrane protein PROM2 is specially regulated by CRM1 and affects the sensitivity of ferroptosis in gastric cancer

  • Gastric Cancer. 2025 Sep;28(5):837-851. doi: 10.1007/s10120-025-01642-6.
Panpan Zhang 1,  Wenbo Lin 1,  Ting Wu 2 3,  Shihao Rao 1 4 2,  Danwei Huang 2 5,  Jing Wu 2 5,  Tao Tao 1,  Jingjing Hou 6 7 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Stress Cell Biology, School of Life Sciences, Institute of Gastrointestinal Oncology, School of Medicine, Zhongshan Hospital of Xiamen University, Xiamen University, Xiamen, 361102, Fujian, China.
  • 2 Department of Basic Medicine, School of Medicine, Xiamen University, Xiang'an District, Xiang'an South Road, Xiamen, 361000, China.
  • 3 Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361000, People's Republic of China.
  • 4 Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, 361004, Fujian, China.
  • 5 School of Medicine, Xiamen University, Xiang'an Hospital of Xiamen University, Xiamen, 361102, Fujian, China.
  • 6 State Key Laboratory of Stress Cell Biology, School of Life Sciences, Institute of Gastrointestinal Oncology, School of Medicine, Zhongshan Hospital of Xiamen University, Xiamen University, Xiamen, 361102, Fujian, China. jjhou@xmu.edu.cn.
  • 7 Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, 361004, Fujian, China. jjhou@xmu.edu.cn.
  • 8 Department of Basic Medicine, School of Medicine, Xiamen University, Xiang'an District, Xiang'an South Road, Xiamen, 361000, China. jjhou@xmu.edu.cn.
PMID: 40679705 DOI: 10.1007/s10120-025-01642-6
Abstract

Background: Gastric Cancer (GC) exhibits high mortality and poor prognosis, with Ferroptosis playing a critical role in its progression. More recent research suggests that PROM2 are closely associated with MVBs (Multivesicular Bodies) which is essential to Ferroptosis, and may represent key molecules involved in the resistance of tumor cells to Ferroptosis.

Methods: The study employed RSL3-induced Ferroptosis models to analyze mitochondrial damage, ROS accumulation, and iron dysregulation. PROM2 expression was assessed under varying RSL3 concentrations and durations. Co-immunoprecipitation and structural modeling elucidated the CRM1-PROM2 interaction. Clinical correlations were evaluated using GC tissue samples. In vivo animal experiments tested the effects of PROM2 and CRM1 inhibition on tumor growth.

Results: RSL3 inhibits cell proliferation and induces Ferroptosis in GC cells, concomitant with increased PROM2 expression. PROM2 Knockdown potentiates Ferroptosis sensitivity and augments RSL3-induced cell death. Clinically, elevated PROM2 correlates with poor prognosis in GC patients. In vivo, PROM2 inhibition suppresses xenograft tumor growth and enhances Ferroptosis susceptibility. Mechanistically, PROM2 interacts with CRM1 whose inhibition by LMB (Leptomycin B) impairs cell proliferation and promotes Ferroptosis. Nucleocytoplasmic translocation of PROM2 is CRM1-dependent, and CRM1 expression positively correlates with PROM2 in GC tissues. CRM1 depletion synergizes with RSL3 to suppress tumor growth in xenograft models.

Conclusions: These findings delineate a CRM1-PROM2 signaling axis that governs Ferroptosis sensitivity in GC, wherein CRM1-mediated nuclear export of PROM2 during Ferroptosis represents a critical regulatory node. Targeting this axis may offer novel diagnostic and therapeutic strategies for GC and Other malignancies.

Keywords

CRM1; Exportins; Ferroptosis; Gastric cancer; PROM2.

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