4-IPP, a selective MIF inhibitor, causes mitotic catastrophe in thyroid carcinomas

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine implicated in cancer.
• MIF signaling through its receptor CD74 and co-receptor CD44 influences cell proliferation, survival, and metabolism.
• Over-expression of MIF is observed in various human neoplastic cells.

Purpose of the Study:

• To investigate the role of the MIF/CD74 axis in thyroid neoplasms.
• To evaluate the therapeutic potential of targeting MIF/CD74 signaling in thyroid cancer.

Main Methods:

• Analysis of MIF and CD74 co-expression in papillary thyroid carcinoma (PTC) and anaplastic thyroid carcinoma (ATC) biopsy samples.
• Assessment of MIF/CD74 co-expression in thyroid cancer cell lines (TPC-1, HTC-C3, NIM-1, K1).
• Treatment of cell lines with a selective MIF inhibitor (4-IPP) and evaluation of its effects on proliferation, apoptosis, and cell death.

Main Results:

• MIF and CD74 were frequently co-expressed in PTC and universally in ATC samples.
• The MIF inhibitor 4-IPP blocked MIF/CD74 internalization, activated JNK, and inhibited proliferation, inducing apoptosis and mitotic cell death in CD74-positive cells.
• In CD74-negative cells, 4-IPP showed partial reduction in proliferation.
• Coordinated MIF/CD74 expression conferred tumor cell plasticity, enabling escape from cell cycle regulation and stress resistance.

Conclusions:

• The MIF/CD74 axis is a critical factor in the biology of aggressive thyroid neoplasms.
• Targeting the MIF/CD74 pathway represents a promising therapeutic strategy for thyroid cancer.
• Inhibition of MIF/CD74 signaling can overcome therapy resistance by targeting DNA endoreduplication and preventing the proliferation of resistant subpopulations.