Treatment with MAPKAP2 (MK2) inhibitor and DNA methylation inhibitor, 5-aza dC, synergistically triggers apoptosis in hepatocellular carcinoma (HCC) via tristetraprolin (TTP)

TY - JOUR

T1 - Treatment with MAPKAP2 (MK2) inhibitor and DNA methylation inhibitor, 5-aza dC, synergistically triggers apoptosis in hepatocellular carcinoma (HCC) via tristetraprolin (TTP)

AU - Tran, Doan Duy Hai

AU - Koch, Alexandra

AU - Allister, Aldrige

AU - Saran, Shashank

AU - Ewald, Florian

AU - Koch, Martina

AU - Nashan, Björn

AU - Tamura, Teruko

N1 - Copyright © 2016 Elsevier Inc. All rights reserved.

PY - 2016/12

Y1 - 2016/12

N2 - Over 100 putative driver genes that are associated with multiple recurrently altered pathways were detected in hepatocellular carcinoma (HCC), suggesting that multiple pathways will need to be inhibited for any therapeutic method to be effective. In this context, functional modification of the RNA regulating protein, tristetraprolin (TTP) that regulates approximately 2500 genes represents a promising strategy in HCC therapy. Since overexpression of TTP induces cell death in all cell types, it would be useful to target the regulator of TTP. In this study, we applied an inhibitor to MAPKAP2 (MK2) that suppresses TTP function. Importantly, cBIOportal for HCC genomics shows that expression level of the MK2 gene correlates with clinical outcome of HCC. We show that upon treatment with MK2 inhibitor, all 5 HCC cell lines, namely HepG2, Huh7, Hep3B, HLE and HLF, reduced cell growth, especially HepG2 and Hep3B cells underwent apoptosis. Simultaneously, TTP target genes such as c-Myc, IER3 or AKT-1 were downregulated. Depletion of the TTP gene rescued cells from apoptosis and restored the TTP-target mRNA expression in the presence of MK2 inhibitor. Furthermore, MK2 was activated in primary HCC that express TTP at high level. The TTP gene was induced upon treatment with DNA methylation inhibitor, 5-aza dC or interferon in three other cell lines, Huh7, HLE or HLF. Upon treatment with MK2 inhibitor and 5-aza dC or interferon these cells underwent apoptosis. The depletion of TTP in these cells partially rescued them from apoptosis, suggesting that the MK2/TTP pathway plays a role in proliferation and maintenance of HCCs. Notably, under the same conditions human hepatocyte cells (THLE-2) did not undergo apoptosis. These data also suggest that MK2 inhibitor with 5-aza dC or interferon may be a useful tool for therapy against HCC.

AB - Over 100 putative driver genes that are associated with multiple recurrently altered pathways were detected in hepatocellular carcinoma (HCC), suggesting that multiple pathways will need to be inhibited for any therapeutic method to be effective. In this context, functional modification of the RNA regulating protein, tristetraprolin (TTP) that regulates approximately 2500 genes represents a promising strategy in HCC therapy. Since overexpression of TTP induces cell death in all cell types, it would be useful to target the regulator of TTP. In this study, we applied an inhibitor to MAPKAP2 (MK2) that suppresses TTP function. Importantly, cBIOportal for HCC genomics shows that expression level of the MK2 gene correlates with clinical outcome of HCC. We show that upon treatment with MK2 inhibitor, all 5 HCC cell lines, namely HepG2, Huh7, Hep3B, HLE and HLF, reduced cell growth, especially HepG2 and Hep3B cells underwent apoptosis. Simultaneously, TTP target genes such as c-Myc, IER3 or AKT-1 were downregulated. Depletion of the TTP gene rescued cells from apoptosis and restored the TTP-target mRNA expression in the presence of MK2 inhibitor. Furthermore, MK2 was activated in primary HCC that express TTP at high level. The TTP gene was induced upon treatment with DNA methylation inhibitor, 5-aza dC or interferon in three other cell lines, Huh7, HLE or HLF. Upon treatment with MK2 inhibitor and 5-aza dC or interferon these cells underwent apoptosis. The depletion of TTP in these cells partially rescued them from apoptosis, suggesting that the MK2/TTP pathway plays a role in proliferation and maintenance of HCCs. Notably, under the same conditions human hepatocyte cells (THLE-2) did not undergo apoptosis. These data also suggest that MK2 inhibitor with 5-aza dC or interferon may be a useful tool for therapy against HCC.

U2 - 10.1016/j.cellsig.2016.09.002

DO - 10.1016/j.cellsig.2016.09.002

M3 - SCORING: Journal article

C2 - 27619201

VL - 28

SP - 1872

EP - 1880

JO - CELL SIGNAL

JF - CELL SIGNAL

SN - 0898-6568

IS - 12

ER -