RRC ID 37608
Author Varinelli L, Caccia D, Volpi CC, Caccia C, De Bortoli M, Taverna E, Gualeni AV, Leoni V, Gloghini A, Manenti G, Bongarzone I.
Title 4-IPP, a selective MIF inhibitor, causes mitotic catastrophe in thyroid carcinomas.
Journal Endocr Relat Cancer
Abstract Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is over-expressed in several human neoplastic cells. When MIF binds its receptor (CD74) and co-receptor (CD44), it initiates signaling cascades that orchestrate cell proliferation and survival, and it can directly modulate the activity of AMPK. These activities indicate that MIF potentially regulates cell survival and metabolism. We found that MIF was primarily co-expressed with CD74 in 16 out of 23 papillary thyroid carcinoma (PTC) and in all the 27 available anaplastic thyroid carcinoma (ATC) biopsy samples. MIF and CD74 were co-expressed in TPC-1 and HTC-C3 cell lines. The selective MIF inhibitor, 4-iodo-6-phenylpyrimidine (4-IPP), blocked MIF/CD74 internalization, activated JNK, and dose-dependently inhibited proliferation inducing apoptosis and mitotic cell death. In two CD74-negative cell lines, NIM-1 and K1, 4-IPP treatment partially reduced proliferation. Coordinated MIF and CD74 expression appeared to confer in tumor cells the plasticity necessary to escape cell cycle regulation, metabolic changes, and stress conditions. MIF/CD74 signaling removal made cells susceptible to apoptosis and mitotic cell death. This finding suggests a possible avenue for targeting DNA endoreduplication, thus preventing the proliferation of therapy-resistant cell subpopulations. This study highlights MIF/CD74 axis as an important player in the biology of aggressive thyroid neoplasms.
Volume 22(5)
Pages 759-75
Published 2015-10-1
DOI 10.1530/ERC-15-0299
PII ERC-15-0299
PMID 26206776
MeSH Apoptosis Biomarkers, Tumor / metabolism Blotting, Western Carcinoma / drug therapy Carcinoma / metabolism Carcinoma / pathology* Carcinoma, Papillary Cell Cycle Cell Proliferation Chromatography, Liquid / methods Fluorescent Antibody Technique Humans Immunoenzyme Techniques Indoles / pharmacology* Intramolecular Oxidoreductases / antagonists & inhibitors* Intramolecular Oxidoreductases / metabolism Macrophage Migration-Inhibitory Factors / antagonists & inhibitors* Macrophage Migration-Inhibitory Factors / metabolism Metabolome* Mitosis / drug effects* Proteome / analysis* Receptors, Immunologic / metabolism Tandem Mass Spectrometry / methods Thyroid Cancer, Papillary Thyroid Neoplasms / drug therapy Thyroid Neoplasms / metabolism Thyroid Neoplasms / pathology* Tumor Cells, Cultured
IF 4.8
Times Cited 9
Human and Animal Cells HTC/C3(RCB0452)