PO-16 - ASK1 regulates tumor lung metastasis and platelet functions

Apoptosis signal-regulating kinase 1 (ASK1) is a MAP3K in the JNK and p38 MAPK pathways and responds to various stresses. Accumulating evidence indicates that ASK1 plays important roles in tumorigenesis by regulating apoptosis and inflammation. However, little is known about ASK1's roles in tumor metastasis.

To investigate ASK1's roles in tumor metastasis.

We performed experimental lung metastasis model by intravenous injection of Lewis lung carcinoma cells constitutively expressing luciferase (3LL-Luc2 cells). As for the analysis of platelet functions, tail bleeding assay and ferric chloride-induced thrombosis model were utilized.

We measured the transition of luciferase activity of the lung lysates up to 7 days as an indicator of lung metastasis. ASK1-/- mice showed markedly lower luciferase activity as early as 3 hours after injection compared to WT mice; hence ASK1 appears to be involved in the early stage of tumor lung metastasis, which is prior to the extravasation of tumor cells. Platelets aggregate and adhere to tumor cells in the early stage and are known to support hematogenous metastasis. ASK1-/- mice were normal in hematological parameters including platelet number, while analysis by western blot revealed that platelets of ASK1-/- mice exhibited markedly reduced phosphorylation of JNK and p38, both of which have been reported to regulate platelet functions such as platelet aggregation. We found that platelets of ASK1-/- mice were less responsive to specific aggregation agonists and that ASK1-/- mice showed bleeding tendency and defect in thrombosis. These phenotypes were also observed in megakaryocyte and platelet-specific ASK1 deficient mice.

It is suggested that impaired platelet functions caused by ASK1 deficiency in platelets may attenuate tumor lung metastasis.