title: PTEN, but not SHIP and SHIP2, suppresses the PI3K/Akt pathway and induces growth inhibition and apoptosis of myeloma cells.
abstract: Expression of PTEN tumor suppressor gene has been known to dephosphorylate the phosphatidylinositol 3' kinase (PI3K) products on the 3 prime inositol ring, resulting in reduced Akt activation. Loss of PTEN expression in OPM2 and delta47 human myeloma lines led to high Akt activity toward insulin-like growth factor I (IGF-I). In contrast, mouse plasma cell tumor (PCT) lines, expressing wild type PTEN, did not respond to IGF-I for Akt activation. We demonstrated here that endogenous PTEN played a negative role in controlling Akt activity in both mouse PCT and NIH3T3 fibroblast lines by using anti-sense oligonucleotides against PTEN. To determine the role of src-homology 2-containing inositol 5' phosphatase (SHIP) in regulating the PI3K/Akt pathway, we manipulated its expression by down-regulation and overexpression in myeloma, PCT and NIH3T3 lines and analysed Akt activation. Our results showed that SHIP, unlike PTEN, did not affect Akt activity in all systems analysed, despite its ability to dephosphorylate a PI3K product. Although SHIP2 expression resulted in suppression of interleukin-6-mediated mitogen-activated protein kinase activation, expression of SHIP and SHIP2 in a PTEN-null myeloma line did not suppress Akt activity. Biologically, expression of only PTEN, but not SHIP and SHIP2, resulted in growth inhibition and increased apoptosis in OPM2 myeloma line. Together, our results have established the role of PTEN, but not SHIP and SHIP2, in negatively regulating the PI3K/Akt cascade and in myeloma leukemogenesis.
authors.affiliation: Lomabardi Cancer Center, Georgetown University Medical Center, Washington, District of Colombia 20007, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Choi
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Cristina
authors.initials: C
authors.lastname: Murga
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Erich
authors.initials: E
authors.lastname: Koller
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: Weiqun
authors.initials: W
authors.lastname: Li
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D015536:Down-Regulation; D005562:Formazans; D016147:Genes, Tumor Suppressor; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012190:Retroviridae; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D015854:Up-Regulation; D018909:src Homology Domains / Q000502:physiology
chemical_list: D017304:Annexin A5; D053148:Caspase 3; D020169:Caspases; D005562:Formazans; D006657:Histones; D007334:Insulin-Like Growth Factor I; D015850:Interleukin-6; D016376:Oligonucleotides, Antisense; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D013778:Tetrazolium Salts; D025521:Tumor Suppressor Proteins; C079782:MTT formazan; C494918:AKT1 protein, human; C494929:PTEN protein, human; C098706:INPPL1 protein, human; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse