Analysis of survival signaling and its application for a new therapeutic strategy of cancers in gastro-intestinal tract and liver.

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Different from another form of cell death called necrosis, a morphological-defined cell death, called apoptosis, has been recently observed. Apoptosis is initiated by death ligands, or by a variety of stimuli including chemotherapy, and y-irradiation.Apoptosis is strictly controlled by a variety of mechanisms at different levels. Inside the cells, the members of Bcl-2 family constitute a first class of regulatory proteins, which act at the mitochondrial level. BAD, a member of Bcl-2 family exerts its pro-apoptotic action on the mitochondrion in the non-phosphorylated state, and forms inactivating dimmers with Bel-XL or Bcl-2 to promote apoptosis. Phosphorylated BAD dissociates from the heterodimeric complex with Bel-XL or Bcl-2,restoring Bel-XL or Bcl-2 function, and activating cell survival signaling. Recent works have indicated that activated BAD kinases including Akt or PKA (A kinase) in the tumor cells play a key role in apoptosis resistance through BAD phosphorylation. We investig … More ated the involvement of intracellular survival signals in human hepatocellular carcinoma(HCC). Both Akt and PKA. were activated in HCCs compared to adjacent non-involved tissues. BAD protein was highly phosphorylated in HCCs compared to uninvolved liver. There was significant correlation between Akt or PKA activity and BAD phosphorylation in HCCs. In addition, inhibitors of these signal transduction cascade induced programmed cell death in human hepatoma cell lines. These observations indicate that survival signal suppresses programmed cell death via BAD phosphorylation in human HCCs, and suggest that it may promote escape from apoptosis to allow HCC tumor progression.On the other hand, mitogen-activated protein kinase(MAPK) cascade is activated in response to various extracellular stimuli. We examined involvement of p38 MAPK, a MAPK super family, cascade in human HCCs and hepatoma cell lines. In HCCs,MKK6,which is upstream of p38 MAPK, and p38 MAPK activities were significantly lower compared to non-tumorous lesions. There was a significant positive correlation between p38 MAPK and MKK6 activity. Moreover, there was a positive correlation between p38 MAPK and caspase-3 activity. HCCs measuring over 20 mm exhibited lower levels of MKK6 and p38 MAPK activity than did smaller tumors. MKK6 transfection increased p38 MAPK activity, cytochrome c release from the mitochondria to the cytosol, and caspase-3 activity, accompanied by apoptosis in hepatoma cell lines. In contrast, a p38 MAPK specific inhibitor prevents MKK6-induced apoptosis in hepatoma cell lines. These results indicate that the p38 MAPK cascade is consistent with induction of a programmed cell death pathway in hepatoma cells, and suggest that reduction of the p38 MAPK cascade may account, in part, for escape from apoptosis, leading to the progression of human HCC.Taking together, the modulation of activated survival signals and diminished apoptotic signals may serve as a new therapeutic strategy for cancer therapy. Less