PTEN induces apoptosis and cell cycle arrest through phosphoinositol-3-kinase/Akt-dependent and -independent pathways

• Published in: Human molecular genetics Vol. 10; no. 3; pp. 237 - 242
• Main Authors: WENG, Liang-Ping, BROWN, Jessica L, ENG, Charis
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.02.2001; Oxford Publishing Limited (England)
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Caspase 9; Caspase Inhibitors; Caspases - metabolism; Cell Cycle - drug effects; Cell Cycle - physiology; Cell Death - drug effects; Cell Division - drug effects; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cysteine Proteinase Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Growth Substances - pharmacology; Humans; Molecular and cellular biology; Phosphatidylinositol 3-Kinases - metabolism; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - physiology; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Tumor Cells, Cultured; Tumor Suppressor Proteins; Human; Signal transduction; Cell line; Shutdown; Enzyme; Protein kinase; Transferases; C-Onc gene; Cell cycle; Protein-tyrosine kinase; Apoptosis; Tumor suppressor gene
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/10.3.237

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.