CEMIP-Mediated ITPR3/CaMKII/NRF2/SLC7A11 Pathway Promotes Ferroptosis Resistance of Prostate Cancer Cells During Extracellular Matrix Detachment

Background: Cells detached from the extracellular matrix (ECM) can trigger different modes of cell death. Ferroptosis, an iron-dependent form of programmed cell death, has recently been found to be involved in matrix-detached cancer cells. However, the molecular mechanisms by which ECM-detached cells escape ferroptosis are not fully understood. Methods: We established the detachment-resistant (DR) PCa cell models by continuous suspension culture, then we examined the effects and mechanism of Cell migration-inducing protein (CEMIP) on ferroptosis in DR PCa cells and their parental cells both in vitro and in vivo. Findings: CEMIP upregulation facilitates ferroptosis resistance of prostate cancer cells during extracellular matrix detachment by promoting cystine uptake. Mechanistically, the interaction of CEMIP with inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) modulates calcium ion (Ca 2+ ) leakage from the endoplasmic reticulum (ER), activating calcium/calmodulin-dependent protein kinase II (CaMKII). Functional studies revealed that CaMKII facilitates nuclear factor erythroid 2-related factor 2 (NRF2) phosphorylation and nuclear localization, leading to elevated transcription of solute carrier family 7 member 11 (SLC7A11), a glutamate/cystine antiporter, in PCa cells. Interpretation: Our study demonstrates a new function of CEMIP in ferroptosis resistance, and suggests CEMIP as a therapeutic target for metastatic PCa. Funding: National Natural Science Foundation of China (81974399 and 81772751). Declaration of Interest: The authors declare no competing interests. Ethical Approval: Research protocols were approved by the Research Ethics Committees of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology.