Ethacrynic Acid Inhibits Sphingosylphosphorylcholine-Induced Keratin 8 Phosphorylation and Reorganization via Transglutaminase-2 Inhibition.
Sphingosylphosphorylcholine (SPC) is significantly increased in the malicious ascites of tumor patients and induces perinuclear reorganization of keratin 8 (K8) filaments in PANC-1 cells. The reorganization contributes to the viscoelasticity of metastatic cancer cells resulting in increased migration. Recently, we reported that transglutaminase-2 (Tgase-2) is involved in SPC-induced K8 phosphorylation and reorganization. However, effects of Tgase-2 inhibitors on SPC-induced K8 phosphorylation and reorganization were not clearly studied. We found that ethacrynic acid (ECA) concentration-dependently inhibited Tgase-2. Therefore, we examined the effects of ECA on SPC-induced K8 phosphorylation and reorganization. ECA concentration-dependently suppressed the SPC-induced phosphorylation and perinuclear reorganization of K8. ECA also suppressed the SPC-induced migration and invasion. SPC induced JNK activation through Tgase-2 expression and ECA suppressed the activation and expression of JNK in PANC-1 cells. These results suggested that ECA might be useful to control Tgase-2 dependent metastasis of cancer cells such as pancreatic cancer and lung cancers.
College of Pharmacy, Dongguk University, Seoul 100-715.
Hyun Jung
HJ
Byun
Kyung Jin
KJ
Kang
Mi Kyung
MK
Park
Hye Ja
HJ
Lee
June Hee
JH
Kang
Eun Ji
EJ
Lee
You Ri
YR
Kim
Hyun Ji
HJ
Kim
Young Woo
YW
Kim
Kyung Chae
KC
Jung
Soo Youl
SY
Kim
Chang Hoon
CH
Lee
Ethacrynic acid; Invasion; Keratin-8 phosphorylation and reorganization; Migration; Sphingosylphosphorylcholine; Transglutaminase-2