Showing papers on "Autophagosome membrane published in 2005"

Expression of the tumor suppressor gene ARHI induces autophagic cell death in ovarian cancer cells

Abstract: Proc Amer Assoc Cancer Res, Volume 46, 2005 844 ARHI, a Ras superfamily member, is expressed in normal ovarian epithelial cells, but markedly downregulated or lost in the majority of ovarian cancers. Introduction of this gene, by adenovirus-ARHI infection into cancer cells that lack ARHI expression inhibits cancer cell growth and motility, and triggers caspase-independent apoptosis. The mechanism by which ARHI inhibits ovarian cancer growth is still not clear. In the present study, we explored ARHI induced autophagy using a stable Tet-On SKOv3-ARHI inducible ovarian cancer cell line. Inducing modest expression of ARHI in SKOv3 cells markedly inhibited cancer cell proliferation, triggered G2M cell cycle arrest, and induced cell death. The growth arrest by induction of ARHI was accompanied by several specific features characteristic of autophagy in a time-dependent manner: 1) presence of numerous autophagic vacuoles in the cytoplasm, 2) development of acidic vesicular organelles, and 3) markedly increased expression of autophagosome membrane specific microtubular-associated protein light chain 3 protein (LC3-I and LC3-II). Electron microscopy revealed typical morphology and ultrastructural changes indicative of autophagic cell death. In contrast, only a few percent of cells developed apoptosis at 4 days after induction. Consistent with our previous data that the N-terminal plays an important role in ARHI induced cell growth, the N-terminal deletion (NTD) mutant ARHI produced very modest growth inhibition and a mild autophagic effect. Together, these findings show that a Ras family member and a tumor suppressor gene ARHI induces cell death in ovarian cancer cells through a mechanism of autophagic cell death, a mechanism distinct from apoptosis. Understanding this unique pathway would provide a novel insight on the therapy of ovarian cancers that are chemoresistant on the basis of ineffective apoptosis.