title: PTEN induces apoptosis and cell cycle arrest through phosphoinositol-3-kinase/Akt-dependent and -independent pathways.
abstract: The tumour suppressor PTEN inhibits cell growth through multiple mechanisms. We have previously demonstrated that overexpression of PTEN in MCF-7 breast cancer cells causes G(1) arrest followed by cell death, the latter of which is believed to be mediated by the phosphoinositol-3-kinase (PI3K) and Akt/PKB pro-apoptotic pathways. In this present study, we show that culture in the presence of low levels of growth factors increased PTEN-mediated growth suppression through the enhancement of PTEN-induced cell death. The caspase 9-specific inhibitor, ZVAD, blocked PTEN-induced cell death without altering the effect of PTEN on cell cycle distribution. Depending on the level of expression, overexpression of dominant-negative Akt induces more cell death and has less effect on the cell cycle or induces similar or decreased cell death without affecting the cell cycle compared with effects on cell death and the cell cycle when overexpressing PTEN. These observations in sum suggest that, in MCF-7 breast cancer cells, the apoptotic cells induced by the overexpression of PTEN did not derive from the G(1)-arrested cells. Further, the effect of PTEN on cell death is mediated through the PI3K/Akt pathway whereas PTEN-mediated cell cycle arrests are through PI3K/Akt-dependent and -independent pathways.
authors.affiliation: Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: L
authors.initials: L
authors.lastname: Weng
authors.forename: J
authors.initials: J
authors.lastname: Brown
authors.forename: C
authors.initials: C
authors.lastname: Eng
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases; D015853:Cysteine Proteinase Inhibitors; D006133:Growth Substances; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C494918:AKT1 protein, human; C494929:PTEN protein, human; C506433:CASP9 protein, human