title: mLST8 Promotes mTOR-Mediated Tumor Progression.
abstract: The activity of the mechanistic target of rapamycin (mTOR) is elevated in various types of human cancers, implicating a role in tumor progression. However, the molecular mechanisms underlying mTOR upregulation remain unclear. In this study, we found that the expression of mLST8, a required subunit of both mTOR complex 1 (mTORC1) and complex 2 (mTORC2), was upregulated in several human colon and prostate cancer cell lines and tissues. Knockdown of mLST8 significantly suppressed mTORC1 and mTORC2 complex formation, and it also inhibited tumor growth and invasiveness in human colon carcinoma (HCT116) and prostate cancer (LNCaP) cells. Overexpression of mLST8 induced anchorage-independent cell growth in normal epithelial cells (HaCaT), although mLST8 knockdown had no effect on normal cell growth. mLST8 knockdown reduced mTORC2-mediated phosphorylation of AKT in both cancer and normal cells, whereas it potently inhibited mTORC1-mediated phosphorylation of 4E-BP1 specifically in cancer cells. These results suggest that mLST8 plays distinct roles in normal and cancer cells, depending upon its expression level, and that mLST8 upregulation may contribute to tumor progression by constitutively activating both the mTORC1 and mTORC2 pathways.
authors.affiliation: Department of Oncogene Research, Research Institute for Microbial Disease, Osaka, University, Suita, Osaka, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kakumoto
authors.affiliation: Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Ikeda
authors.affiliation: Department of Oncogene Research, Research Institute for Microbial Disease, Osaka, University, Suita, Osaka, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Morii
authors.affiliation: Department of Oncogene Research, Research Institute for Microbial Disease, Osaka, University, Suita, Osaka, Japan.
authors.forename: Chitose
authors.initials: C
authors.lastname: Oneyama
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008807:Mice, Inbred BALB C; D046912:Multiprotein Complexes / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics; D000076242:mTOR Associated Protein, LST8 Homolog
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C555285:MLST8 protein, human; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D000076242:mTOR Associated Protein, LST8 Homolog; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases