Parkin Induces MMP-3 Expression in Human Cervical Cancer Cells

초록

Parkin is known to be a tumor suppressor protein. Previously, we determined that parkin expression restoressusceptibility to TNF-α-induced death of HeLa cells, a human cervical cancer cell line resistant to TNF-α-induced celldeath. MMP-3 is a zinc-dependent protease recently reported to activate intracellular apoptotic signaling. In this studywe examined the regulation of MMP-3 expression by parkin in TNF-α-treated HeLa cells. Furthermore, we investigatedthe signaling pathway involved in parkin-induced expression of MMP-3. We found that HeLa cells exhibit low levels ofMMP-3 but is induced after introduction of the parkin gene into HeLa cells. Furthermore, MMP-3 expression increasedfurther when parkin expressing cells were treated with TNF-α. Using chemical inhibitors of cell signaling pathways, wefound that MEK-1 (PD98059), PI3K (LY294002), p38 MAPK (SB203580), and JNK inhibitors alleviated parkin-inducedup-regulation of MMP-3. Finally, we show that TNF-α-induced cell death in parkin expressing cells is inhibited byusing a MMP-3 inhibitor. These results suggest that parkin expression induces prolonged expression of MMP-3 viaMEK-1, PI3K, MAPK, and JNK pathway in HeLa cells allowing the HeLa cells to become sensitive to TNF-α-inducedcell death. These results implicate a role of MMP-3 in parkin-induced cell death in TNF-α treated HeLa cells.

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