Basic research of annexin V as a molecular target therapy for gynecologic cancer

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Recently, molecular mechanism of proliferation and progression of carcinoma cells (infiltration and invasion) has been well understood. As a result, molecular target therapy of cancer patient is developing in Europe and the United States. Clinical trials of some tyrosine kinase inhibitors have already carried out as anti -cancer drugs. Although protein kinase C (PKC) representing Ser/Thr protein kinases is one of the most important kinases, no endogenous inhibitor in the cell has not been discovered. We first separated and purified annexin V from human placenta, which was a Ca^<2+>-dependent phospholipid binding protein, and reported to inhibite protein kinase C activity in vitro. The purpose of this study is to elucidate the role of annexin V in the cell and to clarify whether annexin V can inhibit tumor progression in the cell, followed by developing molecular target therapy of cancer patients with Ser/Thr protein kinase inhibitors by inhibiting tumor progression.We constructed annex … More in V-stably expressing human leukemia cell lines (HL-60). Although annexin V overexpression did not induce morphological changes in the cell lines, TPA-induced PKC activation was inhibited in annexin V overexpressing cells. We showed that PKCδ was a most likely, candidate of TPA targeting PKC isoforms that was inhibited by annexin V. Since annexin V overexpress ion did not induce phenotype, we approached biological function of annexin V by the elucidation of annexin V gene regulation. Our results suggest that (i)protein synthesis inhibitors (CHX, ANI) superinduce annexin V mRNA expression. (ii)TPA enhances CHX-induced the superinduction of annexin V mRNA in MCAS cells by activating PKC and mRNA transcription. (iii)ANI superinduces annexin V mRNA expression through the ERK1/2 MAPK pathway, but not through the p38 MAPK pathway. Taken together, these results indicated that the regulation of annexin V gene expression was negatively controlled at the transcription factor level, and that PKC and ERK1/2 pathway was involved in the induction of annexin V gene expression. Less