TY - JOUR
T1 - TGFb-Induced Lung Cancer Cell Migration Is NR4A1-Dependent
AU - Hedrick, Erik
AU - Mohankumar, Kumaravel
AU - Safe, Stephen
N1 - Funding Information:
The financial assistance of the NIH (P30-ES023512, to S. Safe), Texas AgriLife Research (to S. Safe), and Sid Kyle Chair Endowment (to S. Safe) is gratefully acknowledged.
Publisher Copyright:
©2018 American Association for Cancer Research.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - TGFb induces migration of lung cancer cells (A549, H460, and H1299), dependent on activation of c-Jun N-terminal kinase (JNK1), and is inhibited by the JNK1 inhibitor SP600125. Moreover, TGFb-induced migration of the cells is also blocked by the nuclear export inhibitor leptomycin B (LMB) and the orphan nuclear receptor 4A1 (NR4A1) ligand 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (CDIM8), which retains NR4A1 in the nucleus. Subsequent analysis showed that the TGFb/TGFb receptor/PKA/MKK4 and -7/JNK pathway cascade phosphorylates and induces nuclear export of NR4A1, which in turn forms an active complex with Axin2, Arkadia (RNF111), and RNF12 (RLIM) to induce proteasome-dependent degradation of SMAD7 and enhance lung cancer cell migration. Thus, NR4A1 also plays an integral role in mediating TGFb-induced lung cancer invasion, and the NR4A1 ligand CDIM8, which binds nuclear NR4A1, represents a novel therapeutic approach for TGFb-induced blocking of lung cancer migration/ invasion.
AB - TGFb induces migration of lung cancer cells (A549, H460, and H1299), dependent on activation of c-Jun N-terminal kinase (JNK1), and is inhibited by the JNK1 inhibitor SP600125. Moreover, TGFb-induced migration of the cells is also blocked by the nuclear export inhibitor leptomycin B (LMB) and the orphan nuclear receptor 4A1 (NR4A1) ligand 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (CDIM8), which retains NR4A1 in the nucleus. Subsequent analysis showed that the TGFb/TGFb receptor/PKA/MKK4 and -7/JNK pathway cascade phosphorylates and induces nuclear export of NR4A1, which in turn forms an active complex with Axin2, Arkadia (RNF111), and RNF12 (RLIM) to induce proteasome-dependent degradation of SMAD7 and enhance lung cancer cell migration. Thus, NR4A1 also plays an integral role in mediating TGFb-induced lung cancer invasion, and the NR4A1 ligand CDIM8, which binds nuclear NR4A1, represents a novel therapeutic approach for TGFb-induced blocking of lung cancer migration/ invasion.
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U2 - 10.1158/1541-7786.MCR-18-0366
DO - 10.1158/1541-7786.MCR-18-0366
M3 - Article
C2 - 30072581
AN - SCOPUS:85060401523
SN - 1541-7786
VL - 16
SP - 1991
EP - 2002
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 12
ER -