CCAAT/Enhancer-binding Protein-Homologous Protein Sensitizes to SU5416 by Modulating p21 and PI3K/Akt Signal Pathway in FRO Anaplastic Thyroid Carcinoma Cells

Abstract

SU5416, vascular endothelial cell growth factor receptor inhibitor, suppresses hypoxia-induced angiogenesis, growth, proliferation, and metastasis in cancer cells. CCAAT/enhancer-binding protein-homologous protein (CHOP) has pivotal roles in regulation of growth and survival. In the present study, we evaluated the effects of SU5416 on cell survival, p21, and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma (ATC) cells. Moreover, we investigated the roles of CHOP in cell survival under condition of SU5416 treatment in FRO ATC cells. After SU5416 treatment, cell viability, PARP-1, and caspase-3 protein levels were not changed. p53 and p27 protein levels decreased while p21 protein levels increased. Phospho-Akt protein levels were not altered. In SU5416-treated situation, cell viability was not different before and after administration of either p21 siRNA or LY294002 whereas it was lessened after co-administration of p21 siRNA and LY294002. Compared to SU5416 treatment alone, cell viability was reduced with CHOP plasmid but it was unchanged with CHOP siRNA. PARP-1 and caspase-3 protein levels with CHOP plasmid were elevated whereas the protein levels with CHOP siRNA were similar. While CHOP plasmid transfection diminished p21 and phospho-Akt protein levels, CHOP siRNA transfection did not alter the protein levels. In conclusion, these results suggest that CHOP may sensitize FRO ATC cells to SU5416 thereby inhibiting cell survival by modulating p21 and PI3K/Akt signal pathway. Furthermore, these findings imply that CHOP may be a possible candidate as the chemosensitizing factor for induction of cytotoxicity in ATC cells exposed to SU5416.

Inhibition of p21 and Akt Potentiates SU6656-Induced Caspase-Independent Cell Death in FRO Anaplastic Thyroid Carcinoma Cells

“…Based on our results for p21 and Akt, it is proposed that increased p21 expression and unchanged Akt activity constitute the phenotype of resistance to SU6656-induced cell death in FRO ATC cells. Considering that both SFK inhibition (the present study) and VEGFR inhibition (our previous report) magnify their cytotoxic eff ects on FRO ATC cells through regulation of p21 and PI3K/Akt signaling, it would seem that manipulation of p21 and PI3K/Akt signaling potentiates the therapeutic efficacy of SFK inhibitors and VEGFR inhibitors in ATC [ 23 ] . PI3K/Akt signaling regulates survival in harmony with p21 [ 37 ] .…”

“…There is report that p21 expression decreases in PTC cells with a tendency to undergo early metastasis and another one that p21 expression is not correlated with clinicopathological factors in PTC tissues [ 15 , 32 ] . We found that p21 is associated with resistance to cell death in VEGFR inhibitor-treated FRO ATC cells [ 23 ] . Meanwhile, proteasome inhibitor and epigallocatechin-3-gallate cause cell death in ARO colon cancer cells by increasing p21 levels, and PPARγ agonist exerts an antiproliferative eff ect in ARO colon cancer cells and DRO melanoma cells by increasing p21 levels [ 16 -18 , 33 ] .…”

“…PI3K/Akt signaling, which promotes cell survival, is deregulated in cancer cells including ATC cells [ 19 , 21 ] . We showed previously that PI3K/Akt signaling as well as p21 are involved in the resistance of FRO ATC cells to cell death resulting from VEGFR inhibitor treatment [ 23 ] . SFK modulates PI3K/Akt signaling by modifying PTEN [ 24 ] .…”

“…PI3K/Akt signaling is deregulated in ATC cells, and Akt1 is activated in most ATC patients [ 21 , 22 ] . We reported recently that CCAAT/enhancer-binding protein-homologous protein augments cytotoxicity in vascular endothelial cell growth factor receptor (VEGFR) inhibitor-treated FRO ATC cells by modulating p21 and PI3K/Akt signaling, suggesting that p21 and Akt are associated with resistance to cell death [ 23 ] . SFK regulates PI3K/Akt signaling by altering PTEN [ 24 ] .…”

“…SU6656 has no eff ect on p21 in Panc1 pancreatic cancer cells [ 34 ] . However, because we previously showed the role of p21 in resistance to cell death in VEGFR inhibitor-treated FRO ATC cells, the relationship of p21 with SU6656-induced cell death in FRO ATC cells was clarifi ed [ 23 ] . Our data manifest that SU6656 increases p21 levels concomitantly with cell death and p21 ablation potentiates SU6656-induced cell death in FRO ATC cells.…”