TY - JOUR
T1 - 4-IPP, a selective MIF inhibitor, causes mitotic catastrophe in thyroid carcinomas
AU - Varinelli, Luca
AU - Caccia, Dario
AU - Volpi, Chiara C.
AU - Caccia, Claudio
AU - De Bortoli, Maida
AU - Taverna, Elena
AU - Gualeni, Ambra V.
AU - Leoni, Valerio
AU - Gloghini, Annunziata
AU - Manenti, Giacomo
AU - Bongarzone, Italia
PY - 2015/10/1
Y1 - 2015/10/1
N2 - 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 dosedependently 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.
AB - 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 dosedependently 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.
KW - 4-IPP
KW - AMPK
KW - Anaplastic thyroid carcinoma
KW - CD74
KW - Endoreduplication
KW - Macrophage migration inhibitory factor
KW - Papillary thyroid carcinoma
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U2 - 10.1530/ERC-15-0299
DO - 10.1530/ERC-15-0299
M3 - Article
C2 - 26206776
AN - SCOPUS:84942118130
VL - 22
SP - 759
EP - 775
JO - Endocrine-Related Cancer
JF - Endocrine-Related Cancer
SN - 1351-0088
IS - 5
ER -