2004 Fiscal Year Final Research Report Summary
Pretreatment with PKC Inhibitor enhances TNF-alpha induced apoptosis in TNF-aloha resistant cells and Enhancement of TNF induced antitumor activity by Inhibition of superoxide dismutase induction
| Project/Area Number |
14571649
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Otorhinolaryngology
|
|---|
| Research Institution | Kinki University |
|---|
Principal Investigator |
NISHIDA Shozo Kinki University, School of Pharmaceutical Sciences, 薬学部, 教授 (40208187)
|
|---|
| Project Period (FY) |
2002 – 2004
|
| Keywords | TNFα / PKC / signal transdction / drug resistance |
|---|
| Research Abstract |
Tumor necrosis factor α (TNF-α) modulate various events through several pathways. Many tumor cells are the resistance to this cytokine. Pretreatment of these cells with actinomyucin D enhances TNF-α induced apoptosis. We investigated the mechanism and whether or not apoptosis of TNF-α-resistant cancer cells can be induced by the inhibition of Protein kinase C (PKC). When TNF-a was added after inhibition of PKC by H7, apoptosis was observed, and the activation of nuclear factor kappa B (NF-κB) was also observed. After the inhibition of protein kinase B (Akt) by the LY294002 and p38 mitogen-activqated protein kinase (p38MAPK) by SB203580, the addition of TNF-α did not cause apoptosis. However, after the inhibition of MAPK/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) with U0120, apoptosis was observed when TNF-α was added. In the western blotting anlysis, phosphorylation of MEK1/2 at 60 minutes after the addition of TNF-α. However, it was noted that after pretreatment with H7, a significant decrease in phosphorylated MEK1/2 was observed. The findings of the present experiment suggest that MEK1/2 plays an important role in TNF-α-resistance in TNF-α-resistant B16 melanoma BL6 cells. Furthermore, it was revealed that MEK1/2 was more important than NF-κB, Akt and p38 in anti-apoptotic PKC signaling and that TNF-a-resistance can be overcome by inhibiting MEK1/2. These results suggest the possibility of development of a new anticancer drug treatment.
|
